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PEDIATRICS Vol. 91 No. 2 February 1993 411

SPECIAL

ARTICLES

Extent

of Duplication

in Lower-Limb

Malformations

Suggests

the

Time

of

the

Teratogenic

Insult

David S. Packard, Jr, PhD*; E. Mark Levinsohn, MDX; and David R. Hootnick,

MD*II

ABSTRACT. Investigations of vertebrate limb

develop-ment have suggested that a process called “specification”

instructs the cells of the future limb as to which tissues

they should form. This process proceeds in a wave-like manner, starting at the most proximal levels of the future limb and ending at its distal tip. Human limb specifica-tion probably occurs during the fourth and fifth weeks of development. It is proposed that human limb duplica-tions result from errors of specification and, furthermore, that the more distal the duplication, the later the occur-rence of the teratogenic event during the specification

process. Therefore, among human lower limbs with

du-plications, one may be able to estimate the relative time of the teratogenic event by comparing the levels at which the duplications occur. Pediatrics 1993;91:411-413; lower limbs, teratogenesis.

ABBREVIATION. ZPA, zone of polarizing activity.

The anatomical complexity of human congenital

limb malformations has made it difficult to elucidate

their etiology. Many investigators have focused

at-tention on anatomical information that is readily

ob-tamed by physical and radiographic examination.

This selectivity has resulted in an emphasis on

sur-face anatomy and radiographically visible bony

structures, while abnormalities of the soft tissues

have been relatively underemphasized.13 Similarly,

supernumerary structures in human limbs have

re-ceived little attention.1 We have demonstrated the

importance of performing anatomical studies on all

of the tissues of maiformed limbs4 and have argued that such studies offer important insights into the

mechanisms of teratogenesis.5 Analysis of the

anat-omy of amputated limbs supports our view that the

timing of the teratogenic event determines the final

morphology of the limb.4’5 Other work that we have

performed has demonstrated a consistent association

between a wide variety of congenital bony

deformi-ties of the human lower limb with the absence or

reduction of the anterior tibia! artery and its

derivatives.5’13 The arterial anomalies in these

limbs differed from the other tissue abnormalities in

that they were consistent and independent of the

From the Departments of ‘Anatomy and Cell Biology, Radiology, §Ortho-pedic Surgery, and IlPediatrics, State University of New York Health Science

Center, Syracuse.

Received for publication Jun 11, 1992; accepted Aug 6, 1992.

Reprint requests to (DSP.) Dept. of Anatomy and Cell Biology SUNY Health Science Center, Syracuse, NY 13210.

PEDIATRICS (ISSN 0031 4005). Copyright © 1993 by the American

Acad-emy of Pediatrics.

bony anomalies.5 The remainder of the soft tissues

exhibited anomalies interpreted to be secondary to

the bony anomalies. We believe that this consistently

deficient arterial pattern in the developing limb put

that limb at risk of a subsequent malformation. The

teratogenic event may be initiated by conditions that

jeopardize blood flow through the remaining

arter-ies, leading to tissue damage. This tissue damage

could, in turn, interfere with the developmental

spec-ification or differentiation of limb structures, leading

to bony or soft tissue abnormalities.5

In this paper, we describe our interpretation of

some human limb duplications and explain why we

believe that variations in the timing of single

terato-genic events may influence the extent of the ensuing

limb duplications. Given this interpretation, a

cmi-cian may be able to inspect the morphology of a

malformed limb with duplications and estimate the

relative time during limb development at which the

teratogenic event occurred.

VERTEBRATE LIMB DEVELOPMENT

The vertebrate limb bud is composed of a

meso-derma! core, derived from the flank of the embryo,

and an ectodermal covering.14 A process called

spec-ification instructs the mesodermal cells to form

par-ticular tissues of the limb.15’16 This process proceeds

in a wave-like fashion from the most proximal

por-tion of the developing limb to its distal extent. When

proximal-distal specification of the limb is

experi-mentally halted prior to its completion, the more

distal, unspecified structures do not form.179 The

resulting limb exhibits terminal amputation.

Further-more, the earlier in development specification is

stopped, the more proximal the level of the

amputa-tion.

Specification of the cramal-caudal axis of the limb

is thought to be determined by a group of

mesoder-ma! cells, referred to as the zone of polarizing activity

(ZPA), that reside at the caudal border of the limb

bud.2#{176}The cells of this zone seem to influence

un-specified cells nearest to them to acquire a caudal

identity.21’ Cells that lie more distantly from them

during specification acquire increasingly cranial

identities.23 It has been proposed that the ZPA

influ-ences limb mesoderm cells in this way by producing

a diffusible morphogen whose local concentration

within the limb bud informs the mesodermal cells of

their position along the cranial-caudal axis; that is,

where the concentration of the morphogen is highest, near the ZPA, the cells acquire the most caudal

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Figure. Diagrammatic representation of the bones in four human

lower limbs featuring duplications. We have arranged these limbs according to the level at which the duplicated structures are present, with progressively more distal duplications to the right. We hypothesize that the more distal the supernumerary structures,

the later during the specification period the teratogenic event oc-curred. Therefore, we suggest that the teratogenic events that led to the malformations shown here occurred when developmental specification of the limb reached the level of the future hip, knee,

ankle, and distal foot in limbs A, B, C, and D, respectively. A

Norman W. J Bone Joint Surg. 1964;46-A:1755-1758; B= Narang Iet

a!.JBone Joint Surg. 1982;64-B:206-209; C = Hootnick D et al. Issues Biomed. 1991;14:149-156; D = Leeson M et al. Foot and Ankle.

1985;5:191-197.

412 LOWER-LIMB MALFORMATIONS

tity and where the morphogen concentration is

low-est, farthest from the ZPA at the cranial border of the

limb bud, the cells acquire the most cranial

identi-ty.16’23 If one experimentally grafts a ZPA into the

cranial border of a limb bud, two regions of high

morphogen concentration will form and two caudal

limb borders will be specified.20’24’25 Thus, a

dupli-cation of the limb occurs. Since specification

occur-ring before the intervention was normal, the

proxi-ma! extent of the duplication is likely determined by

the level to which specification had progressed at the

time of intervention.

ANALYSIS OF HUMAN LIMB MALFORMATIONS

We have proposed criteria for classification of hu-man limb defects.4’8’26 These criteria relate the

abnor-ma! morphology of limbs to the time during

devel-opment when a teratogenic event occurred. We term

those defects resulting from a teratogenic insult

oc-curring before or during specification of a particular

part of a limb as “specification defects.” The

com-plete absence of bones and their related soft tissue

structures and/or the presence of supernumerary

structures distinguishes such defects. Malformations

resulting from a teratogenic event occurring after a

particular portion of the limb was specified we term

“postspecification defects.” Such defects feature

mis-shapen, diminished, or absent bony structures

ac-companied by relatively normal soft tissues. In the

case of a missing bone resulting from a

postspecifi-cation insult, an unossified remnant of the bone may

be present.8 If the teratogenic event occurred before

specification was completed, a limb may contain

both types of defects (eg, absent tibia with

diplopo-dia). In such a case, the more proximal portions of the

limb, which contain cells already specified, would

exhibit postspecification defects (eg, misshapen or

absent tibia). The limb distal to the level to which

specification had progressed at the time of the insult

would exhibit the specification defects (eg,

diplopo-dia). Although the presence of different types of

ma!-formations in the same limb may seem to be

con-tradictory, a single teratogenic event occurring at one

moment in time could cause combined

specifica-tion and postspecification malformations in a single

limb.8’26

HYPOTHESIS

In accord with the above interpretation, we

pro-pose that the most proximal level of a duplication

present in a malformed limb suggests the level to

which specification had progressed at the time of the

teratogenic event. The Figure diagrammatically

dem-onstrates the bones of malformed human lower

limbs with successively more distal duplications. We

suggest that these duplications result from

terato-genic events which occurred when limb specification

reached the level of the future hip, knee, ankle, and

distal foot, respectively.

DISCUSSION

The available evidence suggests that human limb

specification occurs during the fourth and fifth

weeks of development.27’28 Most human lower limb

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ii

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congenital abnormalities have anatomical features of

the postspecification type.29 Therefore, most

congen-ital human limb malformations appear to have

re-sulted from teratogenic events which occurred after

the fifth week of development. Accordingly, the

anat-omy of most malformed limbs should not feature

specification defects, ie, the complete absence of

bones and their related soft tissue structures and/or

the presence of preaxial supernumerary structures.

A review of the basic science literature on

verte-brate limb formation suggests three generalities

con-cerning limb duplications that should hold true for

the human lower limb: (1) Duplications, whether of

the limb or part of a digit, will feature two caudal

borders; that is, the portion of the limb or digit that is

duplicated will be double caudal in nature. Double

cranial duplications should be exceedingly rare. (2) If

a portion of a limb or digit is duplicated, the more

distal parts of the limb or digit will also be

dupli-cated. Thus, a limb with fibular dimelia will also

have a duplicated foot or missing foot bones with

missing associated soft tissues. (3) When both

spec-ification and postspecification defects occur in the

same limb, the specification defects should be distal

to the postspecification defects.

Simple postaxial polydactyly, which may be

inher-ited as an autosomal dominant condition, appears to

us to be unrelated to the duplications mentioned

above.30 Postaxial polydactyly does not appear to be

a double caudal duplication. Additionally, postaxial

duplications are relatively minor compared to the

preaxial duplications and not usually associated with

other defects. Such duplications may even reflect

phylogenetic antecedents.333 Occasionally,

bifurca-tion of the distal femur occurs without duplication of

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SPECIAL ARTICLES 413 either the leg or foot.34 This deformity we feel,

re-sults from the postspecification splitting of the distal

femoral growth plate which causes the femur to

ap-pear duplicated distally. Deformities of this type are not specffication defects. One would predict that

in-vestigation of the soft tissues surrounding such a

femoral bifurcation would reveal that the soft tissues

are normal, rather than duplicated. We would be

interested in hearing from physicians who are aware

of other apparent exceptions to these generalizations.

If we are able to estimate the relative time of a

teratogenic event, do we have any insight into the

possible nature of that event? We believe that we

have found evidence that at least some events that

lead to either specification or postspecification

de-fects are vascular. Studies of the arterial pattern in

limbs exhibiting specification and/or

postspecifica-tion defects show deficiency of the anterior tibia!

artery in most cases.4’29 This finding contrasts with

the reported incidence of the same arterial anomaly

in only 2.4% to 7.1 % of normal limbs.35 Since the

arteries appear early in the limb at about the same

time that the cartilaginous models of the bones

ap-pear, and since the vast majority of human limbs that

present bony malformations also present a

consis-tently abnormal arterial pattern, and since the

anat-omy of the arterial anomalies stands out from all the

other soft tissue anomalies, we have concluded that an etiologically significant relationship exists

be-tween the development of the bony and arterial

ab-normalities.9 Thus, we believe the teratogenic event

leading to the malformations described above may,

in some cases, be vascular in nature.

ACKNOWLEDGMENTS

We are grateful to Ors John Fallon, Lewis Holmes, and Leon Kruger for their stimulating discussions and to Dr Lester Fried-man for editing the manuscript. The artwork was expertly pre-pared by Martha Hefner, MS. We gratefully acknowledge the sup-port of University Orthopedics and Sports Medicine, PC of

Syracuse, NY.

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3. Henkel L, Willert H-C. Dysmelia: a classification and a pattern of mal-formation in a group of congenital defects of the limbs. JBone Joint Surg.

1969;51-B:399-414

4. Hootnick DR, Packard OS Jr,Levinsohn EM, Factor D. The anatomy of a human foot with missing toes and reduplication of the hallux. JAnat.

1991;174:1-17

5. Packard DS Jr. Levinsohn EM, Hootnick DR. Teratological implications of soft tissue abnormalities found in human lower limbs with bony defects. Issues Biomed. 1991;14:157-169

6. Hootnick DR. Levinsohn EM, Crider RJ Jr. Packard DS Jr. Congenital arterial malformations associated with clubfoot. Clin Orthop.

1982;167:160-163

7. Hootnick DR. Levinsohn EM, Randall PA, Packard DSJr. Vascular

dys-genesis associated with skeletal dysplasia of the lower limb. JBone Joint Surg. 1980;62A:1123-1129

8. Hootnick DR. Packard DS Jr. Levinsohn EM. Congenital tibial aplasia with preaxial polydactyly: soft tissue anatomy as a clue to teratogenesis.

Teratology. 1983;27:169-179

9. Hootnick DR. Packard DS Jr, Levinsohn EM. Congenital tibial aplasia with preaxial polydactyly: implications of arterial anatomy for abnor-mal limb morphogenesis. In: Limb Development and Regeneration. New York, NY: AR Liss Inc; 1983:327-334

10. Hootnick DR, Packard DS Jr. Levinsohn EM. The etiologic significance of vascular pattern deficiencies in a human limb with diplopodia. Issues Biomed. 1991;14:149-156

11. Sodre H, Filho JL, Napoli MM, Bruschini S. Mestriner LA. Estudo arte-riografico em pacientes portadores de pa torto equinovaro congenito.

Rev Bras Ortop. 1987;22:43-48

12. Sodre H, Bruschini S, Mestriner LA, et al. Arterial abnormalities in talipes equinovarus as assessed by angiography and the doppler tech-nique. JPediatr Orthop. 1990;10:101-105

13. Williams L, Weintroub S. Getty CJM, Pincott JR. Gordon I, Fixsen JA.

Tibial dysplasia: a study of the anatomy. JBone Joint Surg. 1983;65B:157-159

14. Saunders JW Jr. The experimental analysis of chick limb bud develop-ment. In: Ede D, Hinchliffe J, Balls M, eds. Vertebrate Limb and Somite Morphogenesis. New York, NY: Cambridge University Press; 1977:1-24 15. Wolpert L. Positional information and the spatial pattern of cellular

differentiation. JTheor Biol. 1969;25:1-47

16. Slack JMW. From Egg to Embryo. 2nd ed. New York, NY: Cambridge University Press; 1991

17. Summerbell D. A quantitative analysis of the effect of excision of the AER from the chick limb bud. JEmbryo! Exp Morpho!. 1974;32:651-660 18. Saunders JW Jr. The proximodistal sequence of the origin of the parts of

the chick wing and the role of the ectoderm. JExp Zoo!. 1948;108:363-403 19. Rowe D, Fallon J. The proximodistal determination of skeletal parts in

the developing chick leg. JEmbryo! Exp Morpho!. 1982;68:1-7

20. Saunders JW Jr. Gasseling MT Ectodermal-mesenchymal interactions in the origin of limb symmetry. In: Fleischmajer R, Billingham RE, eds.

Epithelia!-Mesenchymal Interactions. Baltimore, MD: Williams & Wilkins; 1968:78-97

21. Hinchliffe JR, Gumpel-Pinot M. Control of maintenance and

anteropos-tenor skeletal differentiation of the anterior mesenchyme of the chick

wing bud by its posterior margin (the ZPA). JEmbryo! Exp Morpho!.

1981;62:63-82

22. Tickle C. Retinoic acid and limb patterning and morphogenesis. In: Hinchliffe JR. Hule JM, Summerbell D, eds. Deve!opmenta! Patterning of the Vertebrate Limb. New York, NY: Plenum Press; 1991:143-149 23. Wolpert L, Lewis J, Summerbell D. Morphogenesis of the vertebrate

limb. Ciba Found Symp. 1975;29:95-130

24. TIckle C, Summerbell D, Wolpert L. Positional signalling and specifica-tion of digits in chick limb morphogenesis. Nature. 1975;254:199-202 25. Fallon JF, Crosby GM. Polarizing zone activity in limb buds of amniotes.

In: Ede D, Hinchliffe J, Balls M, eds. Vertebrate Limb and Somite Morpho-genesis. New York, NY: Cambridge University Press; 1977:55-69 26. Hootnick DR. Packard DSJr, Levinsohn EM, Lebowitz MR. Lubicky JP.

The anatomy of a congenitally short limb with clubfoot and ectrodac-tyly. Terato!ogy. 1984;29:155-164

27. O’Rahilly R, Muller F. Deve!opmenta! Stages in Human Embryos. Carnegie Institution of Washington; 1987. Publication 637

28. Millen J. liming of human congenital malformations. Dev Med Chi!d Neuro!. 1963;5:343-350

29. Levinsohn EM, Hootnick DR. Packard DS Jr. Consistent arterial abnor-malities associated with a variety of congenital malformations of the human lower limb. Invest Radio!. 1991;26:364-373

30. Goldberg MJ. The Dysmorphic Chi!d: An Orthopedic Perspective. New York, NY: Raven Press; 1987:285-291

31. Shubin NH, Alberch P. A morphogenetic approach to the origin and basic organization of the tetrapod limb. Evol Biol. 1986;20:319-387 32. Coates MI, Clack JA. Polydactyly in the earliest known tertapod limbs.

Nature. 1990;347:66-69

33. Gould SJ. Eight (or fewer) little piggies: why do we and most other tertapods have five digits on each limb? Nat Hist. January 1991:22-29 34. Wolfgang CL. Complex congenital anomalies of the lower extremities: femoral bifurcation, tibial hemimelia, and diastasis of the ankle. JBone Joint Surg. 1984;66-A:453-458

35. Sarrafian S. Anatomy of the Foot and Ank!e. Philadelphia, PA: Lippincott; 1983:262

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1993;91;411

Pediatrics

David S. Packard, Jr, E. Mark Levinsohn and David R. Hootnick

Teratogenic Insult

Extent of Duplication in Lower-Limb Malformations Suggests the Time of the

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1993;91;411

Pediatrics

David S. Packard, Jr, E. Mark Levinsohn and David R. Hootnick

Teratogenic Insult

Extent of Duplication in Lower-Limb Malformations Suggests the Time of the

http://pediatrics.aappublications.org/content/91/2/411

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