Skeletal Malformations in Fetuses WithMeckel Syndrome

Klaus Wilbrandt Kjær,1 Birgit Fischer Hansen,1 Jean W. Keeling,2 and Inger Kjær3*1Department of Pathology, Hvidovre University Hospital, Copenhagen, Denmark2Department of Pathology, The Royal Hospital for Sick Children, Edinburgh, Scotland3Department of Orthodontics, School of Dentistry, Faculty of Health Sciences, University of Copenhagen,Copenhagen, Denmark

In six fetuses with Meckel syndrome (gesta-tional age 16–23 weeks, crown-rump length130–170 mm) the skeleton was examined aspart of the autopsy procedure using wholebody radiography and special radiographictechniques. In the upper and lower limbs wefound similar types of polydactyly. We notedfour types, based on the number and mor-phology of metacarpals and metatarsals. Inthe individual fetus there was more oftensimilarity in the pattern of malformation inthe two hands or in the two feet than therewas between the pattern of malformationseen in the hands and that seen in the feet.Only one foot was normal. Malformations ofthe cranial base (the basilar part of the oc-cipital bone or the postsphenoid bone) oc-curred in five cases, and the vertebral bod-ies in the lumbar region of the spine weremalformed (cleft) in three cases. It is pro-posed that a skeletal analysis be included inthe future evaluation of phenotypes inMeckel syndrome. Am. J. Med. Genet. 84:469–475, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: skeletal malformations;Meckel syndrome; polydac-tyly; cranial base; spine

INTRODUCTION

Meckel syndrome (MS) was first described in detailin two sibs by Johann Friedrich Meckel the Younger[1822]. The existence of the syndrome was confirmed in1969 by Opitz and Howe, who proposed the name

Meckel syndrome based on a thorough review of theliterature [Opitz and Howe, 1969]. However, the pa-tient reported by Opitz and Howe [1969] most likelyhad the RSH (“Smith-Lemli-Opitz”) syndrome. Occipi-tal encephalocele, enlarged polycystic kidneys and liverchanges, and polydactyly are the anomalies occurringmost frequently in MS (90%, 100%, and 80%, respec-tively) [Salonen and Paavola, 1998]. MS is an autoso-mal recessive trait [Hsia et al., 1971]. The phenotypevariation is large [Farag et al., 1990; Lurie et al., 1991],and the underlying genotypes are only partly known.In a Finnish population the responsible gene wasmapped at 17q21 [Paavola et al., 1995], but this couldnot be reproduced in other populations [Roume et al.,1997; Paavola et al., 1997]. The incidence varies from1:1,300 among Gujarati Indians [Young et al., 1985] to1: 50,000 among Jews in Israel [Fried, 1973]. MS isusually fatal shortly after birth [Lowry et al., 1983;Coard and Escoffery, 1990].

Studies of MS seldom focus on the skeleton. The mostoften reported skeletal abnormality is postaxial poly-dactyly [Mecke and Passarge, 1971; Fried et al., 1971;Fraser and Lytwyn, 1981; Moerman et al., 1982; Sa-lonen, 1984; Genuardi et al., 1993]. In addition, dys-plastic hipbone and micrognathia have been reported,as well as changes in the humerus, ulna, radius, tibia,or fibula, which are shorter, thicker, and bowed ante-riorly in about one-sixth of all cases [Majewski et al.,1983; Shanks et al., 1997]. Abnormalities in the axialskeleton have not been described.

Our aim was to study the prenatal skeleton in MSand compare the findings with normal skeletal devel-opment. We have employed the definition of Sprangeret al. [1982] of malformation.

MATERIALS AND METHODS

Six human fetuses (gestational age 16–23 weeks,crown-rump length 130–170 mm) were studied follow-ing legal autopsy after prenatal diagnosis of malforma-tion. We could only study the cranial base in the fetuseswhere permission to examine the brain was given. Thephenotype variation of the six cases numbered Case 1to Case 6 is shown in Table I. In two fetuses only theright hands and feet were available for study.

Contract grant sponsor: Danish Medical Research Council;Contract grant sponsor: Vera and Carl Johan Michaelsen Foun-dation; Contract grant sponsor: IMK Almene Fond.

*Correspondence to: Inger Kjær, Department of Orthodontics,School of Dentistry, Faculty of Health Sciences, University ofCopenhagen, 20 Nørre Alle, DK-2200 Copenhagen N, Denmark.

Received 6 January 1999; Accepted 3 February 1999

American Journal of Medical Genetics 84:469–475 (1999)

© 1999 Wiley-Liss, Inc.

The skeletal examination was done by whole bodyradiography and radiography of body segments fromthe cranial base and axial skeleton. A Grenz Ray ra-diographic apparatus (Hewlett Packard Faxitron Se-ries 43805N) was used, with Kodak X-Omat MA filmroutinely processed. The tissue was placed directly onthe film envelope. The tube voltage was 30 kV and,depending on the size of the specimen, the exposuretime varied from 10 to 50 sec at 2.8–3.0 mA. The mid-sagittal segment of the cranial base was radiographedafter being dissected out [Kjær, 1990].

RESULTSAppendicular Skeleton

Tubular bones. The humerus, ulna, radius, fe-mur, and fibula appeared normal. In two cases anteriorbowing of tibia was found.

Hands and feet. All the available hands and feetexcept one foot were malformed with polydactyly. Theycould basically be grouped into two types: Type I, fivenormal metacarpals or metatarsals and an extra fingeror toe with phalangeal bones postaxially, found in onehand (Fig. 1A) and one foot; and Type II, abnormalmetacarpals or metatarsals and varying numbers ofextra fingers or toes with phalangeal bones. Type IIcould be divided into two subgroups: A, fifth metacar-pal or metatarsal malformed and an extra finger or toeplaced postaxially, found in two hands (Fig. 1B) andfour feet (Fig. 2A); and B, an additional metacarpal ormetatarsal present either a, postaxially, seen in fourhands (Fig. 1C) and three feet (Fig. 2B); or b, betweenthe fourth and fifth finger or toe, as registered in threehands (Fig. 1D) and one foot (Fig. 2C).

In four cases (Table II, Cases 1, 2, 3, and 6) the twohands were compared individually, and the two feetwere compared individually. In two fetuses the rightand left hand presented the same type of malformation,and in three fetuses the right and left feet presentedthe same type of malformation.

In five cases (Table II, Cases 1, 2, 3, 5, and 6) thehand was compared with the ipsilateral foot. In one

case, only the right hand and right foot were available.In two fetuses the right hand and right foot presentedthe same type of malformation; on the left side themalformations were never identical in the same indi-vidual.

Trunk

In two cases the vertebral column appeared normalin frontal and lateral view (Fig. 3A,B). We found mal-formations (partial or complete clefts in the vertebralbodies) in the thoracic or lumbar segment of the spinein three fetuses (Fig. 4). One fetus had 13 ribs on theleft side; the others had twelve pairs of ribs.

Cranium

Cranial base. The basilar part of the occipitalbone was normal in one fetus (Fig. 5A). Three fetuseshad malformations in the form of unilateral or bilateralnotching in the basilar part of the occipital bone (Fig.5B). Two bilateral ossification centers in the posteriorpart of the sphenoid bone were found in three fetuses(Figs. 3A and 5A). A centrally placed ossification centerwas found in two cases (Fig. 5B).

Theca and facial skeleton. The bony elements ofthe facial skeleton and nasal bone appeared normal,although the frontal bones were deformed and inclinedbackward (Fig. 3B). In one case a posterior cleft of thepalate was observed. Five fetuses had an occipital en-cephalocele. The sixth had an elongated, cervical clo-sure defect. One fetus had a cerebellar meningocele.The autopsy procedure, with removal of the thecal cra-nium before skeletal analysis, made analysis of the the-cal defect in the region of the encephalocele impossible.

A survey of the individual skeletal findings is pre-sented in Table II.

DISCUSSION

We have described in MS for the first time malfor-mations in the body axis, including the cranial base. Allsix fetuses had malformations in the vertebral columnor in the cranial base.

TABLE I. Phenotypic Variations in Six Human Fetuses With MS

Caseno.

Gestationalage (weeks)

Occipitalencephalocele

Polycystickidneys Polydactyly

Tibialchanges

Proliferationof bile ducts Other

1 19 + + + + Low-set ears, inverted fixed feet, fixedknee-joints

2 23 + + Cervical closure defect, malrotation,situs inversus of heart, right lungthree-lobed, left lung four-lobed

3 18 + + + + + Low-set ears, slight clubfoot on rightside, small lungs, small adrenalglands

4 20 + + + + Cerebellar meningocele, low-set ears,bilateral flexion contracture of crus,malrotation, lung hypoplasia,hypoplasia of frontal cranial bones,cerebellar vermis absent

5 19 + + + + Broad, flat nose, cleft palate,malrotation, pancreas in twofragments, small penis

6 16 + + + + Reduced anterior cranial fossa, lunghypoplasia

470 Kjær et al.

The findings resemble those reported in trisomy 18[Kjær et al., 1996]. In trisomy 18 malformations oc-curred in the vertebral bodies of the lower thoracic andlumbar spine and notching of the basilar part of theoccipital bone occurred, although in trisomy 18 thenotches were sited more rostrally than in MS. To com-pare these similarities in detail, further histologicanalysis is necessary. The malformations found in thevertebral bodies were also similar to those described intrisomy 13 [Kjær et al., 1997], although in trisomy 13the basilar part of the occipital bone appeared normal.Fetuses with trisomy 21 exhibit malformations in thebody axis less commonly [Keeling et al., 1996].

When malformations of the basilar part of the occipi-tal bone are bilateral, they are in trisomy 18 as in MSseemingly found at the same horizontal level. It isknown that the vertebral bodies and the cranial base

are formed around the notochord [Kjær, 1998]. There-fore, it is likely that a malformed area or field in MSextending from the notochord represents an abnormalnotochordal function, which could possibly be related tothe reported malformations in the central nervous sys-tem [Rehder and Labbe, 1981; Paetau et al., 1985;Mamdouha and Claassen, 1990]. In MS it may be as-sumed that there are deviant gene expressions corre-sponding to the area along the body axis where bonymalformations are located.

In the cri-du-chat syndrome it has proved possible toassociate malformations in the clivus with defects inthe cerebellum and dysfunction of the glosspharyngealnerve (the larynx) [Kjær and Niebuhr, 1999]. The threestructures might demarcate a field whose developmentis probably disturbed in cri-du-chat syndrome. Wheth-er the malformations found in MS can be similarly

Fig. 1. Four different polydactyly phenotypes are identified in the right hands of human fetuses with MS. A: Normal number of metacarpals withadditional phalangeal bones; gestational age 20 weeks (Type I). B: Malformed fifth metacarpal with extra phalangeal bones; gestational age 19 weeks(Type IIA). C: Additional metacarpal, located postaxially, with extra phalangeal bones; gestational age 23 weeks (Type IIBa). D: Additional metacarpalbetween fourth and fifth bone (arrow), with additional phalangeal bones; gestational age 19 weeks (Type IIBb).

Skeleton in Meckel Syndrome 471

Fig. 2. Three of four identified polydactic phenotypes in the right feetfrom human fetuses with MS. A: Malformed fifth metatarsal with addi-tional phalangeal bones; gestational age 23 weeks (Type IIA). B: Addi-tional metatarsal located postaxially with extra phalangeal bones; gesta-tional age 18 weeks (Type IIBa). C: Additional metatarsal between fourthand fifth bone (arrow) with additional phalangeal bones; gestational age19 weeks (Type IIBb).

TABLE II. Skeletal Malformations in Six Human Fetuses With MS

Caseno.

Vertebralcolumn

Basilar part ofoccipital bone

Posterior partof sphenoid bone

Handsb Feetb

OtherLeft Right Left Right

1 Malformed NEa NE IIA IIA IIBa I Anteriorly bowed tibia2 Malformed Malformed Normal IIBb IIBa IIA IIA 13 Left ribs3 Malformed Normal Cleft IIBb IIBa IIBa IIBa Anteriorly bowed tibia4 Normal Malformed Cleft NE I NE Normal5 Normal Malformed Normal NE IIBb NE IIBb Posterior cleft palate6 NE NE Cleft IIBa IIBa IIA IIA

aNE, Not evaluated.bI, Five normal metacarpals or metatarsals with extra phalangeal bones postaxially; IIA, Fifth metacarpal or metatarsal malformed with extra phalan-geal bones postaxially; IIBa, Extra metacarpal or metatarsal postaxially with extra phalangeal bones postaxially; IIBb, Extra metacarpal or metatarsalbetween fourth and fifth ray with extra phalangeal bones.

472 Kjær et al.

linked to specific phenotypic traits on the basis of theirlocation is not yet known. Possibly, the clivus malfor-mation in MS could be associated with the occipitalencephalocele malformation.

Our material comprised only six fetuses, and not allof them could be examined completely because of theprevailing regulations governing autopsy permission.It cannot be concluded, therefore, that the malforma-tions described are to be found in all cases of MS.

Hand surgeons often distinguish between radial(first finger), central (second to fourth fingers), and ul-nar (fifth finger) polydactyly. The classification ofTemtamy and McKusick [1978] is based on anatomicalfindings in different syndromes, and distinguishes be-tween preaxial polydactyly (first to second finger) withsubgroups, and postaxial polydactyly (fifth finger) withsubgroups. In MS postaxial polydactyly is common.Majewski [1983] described two cases with preaxial

Fig. 3. Axial skeleton of a human fetus with MS. A: Frontal view. B: Lateral view. Gestational age 19 weeks. Normal appearance of vertebral bodies(curved arrows). Basilar part of occipital bone. O; unilateral notching at the arrowhead. Posterior part of sphenoid bone. S; two ossification centers.Frontal bone, inclined backward (F).

Skeleton in Meckel Syndrome 473

polydactyly (one, in addition, with postaxial polydac-tyly). Schrader [1990] reported a case with postaxialpolydactyly of all limbs, and an extra fourth finger onone hand, explained as caused by extra ulnar mesen-chyme. Based on metacarpal or metatarsal findings, webasically found two types of polydactyly in MS.

The normal development of the limb and chondrifi-cation of the hand and foot proceed in a proximal-distaldirection, which means the formation of metacarpalcartilage before phalangeal cartilage in the fingers, andmetatarsal cartilage before phalangeal cartilage in thetoes [Larsen, 1997]. The normal appearance of ossifi-

cation centers in the hand and foot proceeds in theopposite direction [Kjær, 1974]. In all of our cases ab-normal metacarpals or metatarsals were associatedwith an abnormal number of fingers or toes. Our hy-pothesis is that the extent of the malformation in thehand and foot is greater when metacarpals and meta-tarsals are involved than when they are not. Because ofthe proximal-distal developmental direction of the limbbuds, one cannot expect a normal number of fingers onan increased number of metacarpals, nor a normalnumber of toes on an increased number of metatarsals.

According to Martınez-Frıas et al. [1998], a field in-cluding the fifth ray and the area between the fourthand fifth ray constitutes a secondary developmentalfield. This field of development is disturbed in MS inpolydactyly type IIBb, illustrated in Figures 1D and2C. Interestingly, the demarcation of this field seems tocorrespond to the sensory skin innervation of C8 in thedistal part of the hand via the ulnar nerve, and of S1 inthe foot via the sural nerve. The fate of the differentparts of the limb is determined by the influence of theapical epidermal ridge. Moreover, it is known fromother limb formation studies that the number of ex-pressed HOX genes increases in the proximal-distal di-rection in the limbs [Larsen, 1997], and it is also sug-gested that the field involved in MS has a specificchange in HOX genes.

In the individual fetus there was more often similar-ity in the pattern of malformation in the two hands orin the two feet than there was between the pattern ofmalformation seen in the hands and that seen in thefeet. As the polydactic types of malformations in thehand and foot are similar, the underlying moleculargenetic factors could very well be similar. It will beimportant in future studies to clarify whether the skel-etal defects in the different parts of the body in MS aredue to the same deviations or to different deviations inmolecular genetic factors.

Detailed phenotype determination of the skeleton isimportant for autopsy diagnosis and for intrauterinediagnosis [Nyberg et al., 1990; Wright et al., 1994;Sepulveda et al., 1996]. Genetic counselling based on

Fig. 4. Lateral radiograph of a spine from a human fetus with MS;gestational age 23 weeks. Note malformations (partial or total clefting) ofthoracic and lumbar vertebral bodies, marked with arrows.

Fig. 5. Basilar part of the occipital bone (O) and the posterior part of thesphenoid bone (S) from human fetuses with MS (frontal projection). A:Normal appearance of occipital bone and bilateral ossification centers ofsphenoid bone; gestational age 18 weeks. B: Bilateral notching of occipitalbone (indicated by small arrows) and normal midaxial location of sphenoidbone; gestational age 23 weeks.

474 Kjær et al.

knowledge of the relationships between genotypes andphenotypes is crucial for the parents of children withcongenital malformations. Our findings focus on therelevance of including skeletal changes in the system-atic charting of malformations in MS, and of relatingthese to previously reported malformations.

ACKNOWLEDGMENTS

Contract grant sponsors: The Danish Medical Re-search Council, Vera and Carl Johan Michaelsen Foun-dation, and the “IMK Almene Fond.”

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