American Journal of Medical Genetics 45471-476 (1993)

Skeletal Histopathology in Fetuses With Chondroectodermal Dysplasia (Ellis-van Creveld Syndrome) Faisal Qureshi, Suzanne M. Jacques, Mark I. Evans, Mark P. Johnson, Nelson B. Isada, and S. Samuel Yang Departments of Pathology (F.Q., S.M.J.) and Reproductive Genetics (M.I.E., M.P.J., N.B.I.), Hutzel Hospital and Wayne State University School of Medicine, Detroit, and Department of Pathology, William Beaumont Hospital, Royal Oak (S.S.Y.), Michigan

Chondroectodermal dysplasia (CED) is an un- common autosomal recessive disorder and one of the short rib polydactyly syndromes (SRPS). It is characterized by acromelic and mesomelic shortness of limbs, postaxial poly- dactyly, small chest, ectodermal dysplasia, and in many cases, congenital heart defects. Controversy exists over possible changes in the growth plate. With the advent of ultra- sonographic examination, increasing num- bers of fetuses with osteochondrodysplasias are examined by pathologists. Since histo- pathologic examination of the skeletal system is useful in defining various osteochondro- dysplasias and it has not been described in the fetus with CED, we herein describe 3 cases of fetal CED with emphasis on skeletal histo- pathology. All 3 pregnancies were terminated at 22-23 weeks because of ultrasonographic demonstration of short limbs and growth re- tardation. Radiologically, each fetus had ac- romelic and mesomelic shortness of long bones with smooth round metaphyses, ver- tically short iliac bones, short ribs and normal vertebrae. These findings are similar to those described in the larger newborn infant with CED. Histopathologically, the cartilage of the long bones showed chondrocytic disorganiza- tion in the physeal growth zone. The findings are dissimilar to those of larger infants and older children in whom chondrocytic colum- nization has been seen in the central physis and disorganization in peripheral physis. Fur- thermore, a variable degree of chondrocytic disorganization was also seen in the central physeal growth zone of vertebrae in these fe-

hceived for publication April 13,1992; revision received August 21, 1992.

Address reprint requests to Faisal Qureshi, M.D., Department of Pathology, Hutzel Hospital, 4707 St. Antoine Blvd., Detroit, MI 48201.

tuses. Other findings noted at fetopsy were: polydactyly in all 3 cases, congenital heart defect in 2 and an abnormal frenulum in one case. The foregoing phenotypic and radio- graphic manifestations and skeletal histo- pathology help separate CED from other SRPS. o 1993 wiley-Liss, Inc.

KEY WORDS acromelia, chondrocytic dis- organization, chondroecto- dermal dysplasia, short rib polydactyly syndrome

INTRODUCTION The skeletal histopathology of chondroectodermal

dysplasia (CED) or Ellis-van Creveld syndrome has been studied in newborn infants and older individuals, but has not been described in the fetus. Histopathologic examination of the skeletal system has been helpful in defining various osteochondrodysplasias. As increasing numbers of fetuses with osteochondrodysplasias are be- ing diagnosed antenatally in the second trimester and being submitted to the pathologist for examination, rec- ognition of the histopathologic changes in the skeleton in this period of development has become a necessity. We describe 3 fetuses with CED with special emphasis on the histopathologic features.

CLINICAL REPORTS Case 1

This 320 g male fetus with a gestational age of 22-23 weeks had a crown-heel length of 24.3 cm and a crown- rump length of 18.2 cm. At autopsy, a large atrial septa1 defect of the primum type was present. No other clinical information was available. No other congenital anoma- lies were noted. For anthropometric measurements and polydactyly see Table I.

Case 2 This 23-week-old fetus was delivered to a 22-year-old

G1 mother of Iraqi descent. An initial ultrasound exam-

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472 Qureshi et al.

TABLE I. Extremity Lengths and Other Limb Abnormalities

Uppef Shoulder- Elbow- Lower extremity elbow wrist extremity Hip-knee Knee-heel

Case length . (cm) length (cm) length (cm) length (cm) length (cm) length - (cm) Hands

1 8.4 4.0 NIA 6.7 3.6 NIA Postaxial polydactyly bilateral

polydactyly bilateral

polydactyly bilateral

2 NIA" 5.0 4.0 NIA 5.5 4.5 Postaxial

3 NIA 4.5 3.5 NIA 4.5 4.1 Postaxial

Feet Postaxial

polydactyly right

Postaxial polydacty ly bilateral

Polydact yly not present

a NIA indicates not available.

ination showed the fetus to have short limbs. A repeat ultrasound examination showed a fetus with an esti- mated gestational age of 23 weeks. All the long bones were noted to be less than the 5th centile in length. The thorax was small. A diagnosis of osteochondrodysplasia was made. After counselling, the mother opted for ter- mination of her pregnancy. At fetopsy, the fetus weighed 560 g with a crown-rump length of 21.5 cm and crown- heel length of 29.5 cm. The ears were small and ap- peared rounded. The nasal bridge was flat. The upper lip was small. There was micrognathia along with a mal- formed mandible. The frenulum was small and mal- formed. The hands and fingers were short and stubby. The great toes were very short and the plantar arches were high. No cardiac defects were noted. The left lung was abnormally lobated with incomplete separation of upper and lower lobes. Table I records the anthropo- metric measurements and polydactyly.

Case 3 (Fig. 1) This fetus with an estimated gestational age of 23

weeks was delivered to 20-year-old G1 Iraqi mother. An ultrasound examination showed multiple abnormali- ties. These included an abnormal heart, shortened long bones, asymmetric growth retardation, single umbilical artery and mildly decreased amniotic fluid. The clinical diagnosis was skeletal dysplasia. The mother opted for termination of her pregnancy. At autopsy, the fetus weighed 470 g with a crown-rump length of 21.0 cm and crown-heel length of 29.0 cm. The hands were short with short, stubby fingers. Both hallices were short and both fifth toes were small. The chest was narrow with a cir- cumference of 15.0 cm. A persistent common atrio-ven- tricular canal was noted on examination of the heart. No other internal abnormalities were found. Apart from epicanthal folds and prominent eyes, no other minor anomalies were noted. For anthropometric measure- ments and polydactyly see Table I.

Radiological Changes In 2 cases, xeroradiography was used, this being the

routine in our institution, giving excellent detail of the skeletal system. Case 1 was examined with routine X-ray techniques. All 3 cases showed similar radioloaic

the hand also were apparently short; however, the young age of the fetuses made proper evaluation difficult. Poly- dactyly was seen in all cases, being present in all the upper limbs. It Was also present in both lower limbs in Case 2 and in the :right foot in Case 1. Polydactyly of the lower limbs was nlot seen in Case 3. The iliac bones were square. The acetabular roof had an unusual appearance. The medial socket was convex with an acetabular spur on either side, giving the acetabulum a "trident-like"

- find&. The long bones were short and ap- peared to have a round metaphyseal end. The bones of

Fig. 1. Macerated fetus with postaxial polydactyly of the upper limbs and short limbs.

Chondroectodermal Dysplasia 473

the physis at the level of the zone of proliferation. It appeared thicker and longer than that of the control sections but was not demonstrable radiologically.

DISCUSSION Chondroectodermal dysplasia (CEDI was initially de-

scribed by Ellis and van Creveld [19401 who reported on 3 cases. McKusick et al. [ 19641 studied 52 patients in the old order Amish and not only confirmed the autosomal recessive nature of the syndrome but also further de- fined its clinical picture. This includes polydactyly as a constant finding and short limbs, especially distally. Only one of their cases, a 2-day-old infant, had a post- mortem examination, but histologic studies of the phy- seal growth zone were not reported.

These above studies and most other subsequent re- ports of the syndrome were primarily clinically oriented and did not include the histopathology of the skeletal system. Occasional studies which have addressed the issue in newborn infants have not shown a consistent histopathologic picture. Most of these have been single case reports. Smith and Hand C19581 reported 2 cases noting a thin epiphyseal line with irregularly shaped

appearance. The ribs were short, ending in the midaxill- ary area and showing anterior widening (Fig. 2). The vertebral bodies were normal, as was the skull.

Histopathology of Skeletal System Histologic sections were taken from the proximal end

of the femora, vertebral bodies and the costo-chondral junctions [Yang et al., 19861. We compared these 3 cases with 3 age-matched controls (Fig. 3). Ofthese, the femur and vertebral bodies consistently contained cartilagin- ous tissue including the physeal growth zone. All 3 cases showed similar histopathologic changes. In the femur, there was poor columnization of chondrocytes in the physis, especially in the zone of hypertrophy (Fig. 4). The resting cartilage was normal. In the vertebrae, there was variable but definite chondrocytic disorganization in the central physeal area. In the peripheral physis, there was generally better organization of chondrocytes (Fig. 5). There were no islands of cartilage in the metaphysis. No invasion of the physeal growth zone by fibrous or mesenchymal-like bands of soft tissue was noted. The cartilage matrix of the femora, vertebral bodies, and ribs was unremarkable. Periosteal membranous ossi- fication in the femur extended to the perichondrium of

Fig. 3. Physeal growth zone of the femur from an age-matched control fetus with hypertrophic and proliferative zones organized in columns. Minimal focal disorganization as seen at the right side of the photomicrograph may occasionally be seen.

Fig. 2. Xeroradiograph showing polydactyly, abnormal iliae, short ribs, and rounded metaphyseal ends of the long bones.

474 Qureshi et al.

Fig. 4. Sections of the femur showing disorganization and poor columnization of chondrocytes in the physeal growth zone. No organiza- tion was noted.

lacunae, abnormal chondrocytic nuclei and islands of hyaline cartilage in metaphyseal trabeculae with irreg- ular areas of ossification. Mitchell and Waddell [1958] examined an amputated sixth digit from a 5-year-old girl. They noted decreased numbers of cartilage cells and abortive columnar arrangement of the chondro- cytes. The epiphyseal line was irregular and showed reduced and irregular capillary invasion. Hirokawa and Suzuki [ 19671 described autopsy findings in a 2-day-old term infant. They noted that the hypertrophic cartilage cell columns were short and irregularly aligned. Protru- sions of broad peninsulas of poorly calcified cartilage were present in the spongiosa of the vertebral bodies. Rimoin [19751 studied the rib and iliac crest tissue in one patient. He described a distinctly abnormal resting cartilage with large chondrocytes and multiple chondro- cytes per lacunae. The matrix was fibrous with areas of degeneration and increased vascularity of the cartilage. The physeal growth plate and bony trabeculae appeared unremarkable. The age of this patient was not stated. Bohm et al. 119781 described the cartilage of the femur, tibia and ribs of a 28-month-old boy. They noted that the chondrocytes of the growth plate were reduced in num- ber and arranged in a disorderly pattern. There was

Fig. 5. Sections ofthe vertebral bodies show better organization and columnization of chontdrocytes, especially in the peripheral physis.

irregular vascular resorption of the cartilage with a tongue-shaped metaphyseal border. The histopathologic and radiologic variability of these cases suggests that they may represent variants of CED or one of the SRPS; however, the quality of the reproductions available for review make accurate assessment difficult.

Our 3 cases are the first reported cases of fetal CED with histopathological and radiological correlation. Pre- viously, only rare cases of CED were diagnosed anten- atally, but none has described the histopathology of the skeletal system [ h i et al., 1984, one case; Mahoney and Hobbins, 1977, 2 cases; Zimmer et al., 1984, one case].

All of our cases showed similar histopathologic changes of the cartilage. The major change was chon- drocytic disorganization in the physeal growth zone, consisting of poor alignment and irregularity of the chondrocyte columns. In the vertebral bodies, the cen- tral physeal growth zone showed a variable degree of chondrocytic disorganization with better preservation of normal histology at the periphery. Multiple nuclei per lacuna, increased vascularity or fibrosis of the matrix, as described by Rimoin [19751 were not seen; however, some of the lacunae in Case 1 were prominent. The presence of cartilage islands in the metaphysis as noted

Chondroectodermal Dysplasia 475

19911, but the findings may not be adequately visu- alized in the radiographs. Since the iliae in both entities are dysplastic, separation of these 2 entities may remain unsettled. The presence of focal but unequivocal physeal chondrocytic columnization in the vertebral bodies of CED may be a useful finding, separating it from SR(P)S BL type. In fact, this physeal chondrocytic columniza- tion of CED is not seen in any other SRPS. In SR(P)S BL, the vertebral physeal growth zone is not only disor- ganized, the cartilage bone junction is also prominently serrated and there is a widened zone of provisional calcification.

SRPS, type 2 (Majewski), is an autosomal recessive condition. The radiologic changes of limb bones and ver- tebral bodies in this entity are similar to those of CED. Polydactyly is also a constant finding, although it may be preaxial. However, rib shortness in this entity is extreme. Furthermore, the iliae are normal radiologi- cally and the tibiae are shorter than the fibulae with an oval or rounded configuration. There is no physeal chon- drocytic columnization as seen in CED.

In summary, the fetuses with CED have chrondocytic disorganization of the physeal growth zone of the long bones with variable organization in the vertebrae. These changes, in conjunction with the radiologic find- ings, help to differentiate fetal CED from other SRPS.

by others [Smith and Hand, 1958; Hirokawa and Suz- uki, 19671 was not observed in any of our cases. Al- though there are differences in the histopathology of the growth plate between our three cases and those reported before, these may partly be explained by the differences in the ages of our subjects and their patients. All our cases were fetuses at 23-24 weeks of gestation while the other reported cases were infants or older children.

Radiologically, all of our cases were markedly similar. The acromelic and mesomelic shortness of the limbs, polydactyly, abnormal iliac bones and short ribs seen in these fetuses were similar to the findings previously described in newborn infants and older children [Maro- teaux, 1979; Spranger et al., 19741.

The separation of CED from other SRPS can be diffi- cult at times since there is an overlap of the clinical and radiological findings in some of these syndromes. It is in these instances that histopathology is of value. Three syndromes in the SRPS that may mimic CED are: as- phyxiating thoracic dystrophy (ATD) type 2, SR(P)S Beemer-Langer type (SR(P)S BL) and SRPS type 2 (Ma- jewski). Although Spranger and Maroteaux [19901 at- tempted to refine the classification of SRPS’s, the Inter- national Nomenclature of Constitutional Diseases of Bone [1983] is used in this discussion.

Perhaps most difficult to differentiate from CED at an early gestational age is ATD type 2. It is also an autoso- ma1 recessive condition. Death from respiratory insuffi- ciency is common, and surviving infants may develop progressive renal disease [Langer, 19681. Previous au- thors [Maroteaux and Savart, 1964; Langer, 1968; Yang et al., 19871 have noted the clinical and radiologic sim- ilarities between these 2 syndromes. However, polydac- tyly is rarely, if ever, seen in ATD type 2, while it is constantly seen in CED. Histopathologically, ATD type 2 shows retarded and disorganized enchondral ossifica- tion throughout all physeal growth zones in contrast to the presence of chondrocytic columnization in the pe- ripheral vertebral cartilage as reported here. In 3 of their cases of ATD type 2 [Yang et al., 19871, the car- tilage columns in the metaphysis of proximal femora formed a lattice network, and in another case there was irregular vascular penetration of the physeal cartilage. Distinguishing CED from ATD type 1 is not as difficult, since the latter condition shows irregular metaphyseal ends radiologically and patchy endochondral ossifica- tion in the tubular bones with an irregular cartilage bone junction histopathologically. The foregoing find- ings of ATD type 1 are also not seen in ATD type 2.

SR(P)S Beemer-Langer (SR(P)S BL) type is probably an autosomal recessive disorder [Yang et al., 19911. Ra- diologically, the limb bones and ribs of this entity are qualitatively similar to those of CED. The rib shortness in SR(P)S BL type is more extreme and the radii and ulnae are bowed; therefore separation of the 2 is not difficult. Occasionally the foregoing difference may not be very prominent and if there is polydactyly, the sep- aration of this entity from CED may be difficult. The small, relatively poorly ossified vertebrae with in- creased intervertebral spaces, thoracic lordosis, small scapulae, and short tubular bones of hands and feet seen in SR(P)S BL help to separate it from CED [Yang et al.,

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