American Journal of Medical Genetics 56:300-303 (1995)

Histopathology of Fetal Diastrophic Dysplasia

F. Qureshi, S.M. Jacques, S.F. Johnson, M.P. Johnson, R.F. Hume, M.I. Evans, and S.S. Yang Departments of Pathology (F.Q., S.M. J.) and Obstetrics and Gynecology (M.P. J., R.F.H., M.I.E.), Hutzel Hospital and Wa-yne State University, Detroit, William Beaumont Hospital (S.S.Y.), Royal Oak, Michigan, and Children’s Hospital of Oklahoma (S.F.J.), Oklahoma City, Oklahoma

We report on three cases of diastrophic dys- plasia in second trimester fetuses and dis- cuss the differential diagnosis and clinical, radiologic, and histopathologic findings. Manifestations of typical diastrophic dys- plasia in infants and older patients include abnormal pinnae, scoliosis, and joint con- tractures; these were absent in the fetuses, in keeping with the tendency for the clini- cal and radiologic aspects of this disease to become more severe with age. The histo- pathologic characteristics of the cartilage appear to be similar in the fetus and older patient, and therefore may be useful in dif- ferentiating diastrophic dysplasia from other osteochondrodysplasias in the sec- ond trimester. @ 1995 WiIey-Liss, Inc.

KEY WORDS: osteochondrodysplasias, di- astrophic dysplasia, autoso- ma1 recessive inheritance

INTRODUCTION Diastrophic dysplasia (DD) is an autosomal recessive

disorder with well-defined clinical, radiologic, and pathologic manifestations, although the degree of ex- pression may vary [Horton et al., 19781. Characteristi- cally it is associated with shortness of the limbs, meta- physeal flare, hitchhiker thumbs, clubhands, clubfeet, joint contractures, progressive scoliosis, and abnormal pinnae. While this typical clinicopathologic picture of DD is usually easy to diagnose in the infant or young child, it is more difficult to diagnose in a second trimester fetus, since many of the above abnormalities may not have developed. However, recently the diagno- sis of DD in the fetus in utero is being made with in- creasing frequency by ultrasonography [OBrien et al., 1980; Mantagos et al., 1981; Gollop and Eigier, 1987; Gembruch et al., 19881. None of these previous studies

Received for publication June 5, 1994; revision received No- vember 4.1994.

Address reprint requests to Dr. F. Qureshi, Department of Pathology, Hutzel Hospital, 4707 Saint Antoine Boulevard, De- troit, MI 48201.

0 1995 Wiley-Liss, Inc.

has included histopathological examination of the carti- lage. Such examination is often useful in diagnosing osteochondrodysplasias, since the histopathological ap- pearance of the cartilage in the fetus may not necessar- ily be the same as that of the newborn infant or older patient in these disorders [Qureshi et al., 19931. We pre- sent three cases of fetal DD and discuss the histopatho- logic and radiologic aspects of the skeletal system and discuss the differential diagnosis of this condition.

MATERIALS AND METHODS ‘Three cases of fetal DD were identified in the files of

the Departments of Pathology of Hutzel Hospital and Children’s Hospital of Oklahoma. In all three cases the diagnosis of osteochondrodysplasia was made on ultra- soinography, and the pregnancy was terminated follow- ing genetic counseling. A complete autopsy, including radiologic and histopathologic studies of the skeletal syistem, was performed in each case. In two cases xe- roieadiography was performed, since it was thought that this would provide greater detail of the bone struc- ture. In the third case conventional radiographic exam- ination was employed. In each case the femora, humeri, vertebral bodies, and ribs were examined according to thl. method described by Yang et al. [1986]. In two caises, sections of the trachea were also available for study. Special stains, including alcian blue at pH 1.0, Gomori’s Trichrome and PAS with and without diastase were done on the cartilage.

CLINICAL HISTORIES (Table I) Case 1

‘This fetus was delivered to a 26-year-old gravida 3, para 1, abortus 1 mother following therapeutic termi- nation of pregnancy. An ultrasound examination done earlier in pregnancy had demonstrated limb abnormal- itiles, and a diagnosis of osteochondrodysplasia was made. The family history was unremarkable.

Case 2 (Fig. 1) ‘This fetus was delivered to a 37-year-old gravida 1,

mother following therapeutic termination of pregnancy. A prenatal ultrasound examination at 20 weeks of ges- talion had shown severe osteochondrodysplasia. The fainily history was significant for a paternal grand- mother with short digits and a paternal great aunt with short stature.

Diastrophic Dysplasia 301

TABLE I. Clinical Features and Autopsy Findings in the DD Fetuses

Gestational age Case number (weeks) Chromosomal analysis Skeletal findings Other findings

1 20-21 46,XY

2 23% 46,XY

3 22% 46.XY

Micromelia Hypertelorism Backward sacral tilt Micrognathia Hitchhiker thumbs Micromelia Low-set ears Hitchhiker thumbs Hypertelorism Clubfeet High-arched palate Micromelia Micrognathia Hitchhiker thumbs Clubfeet

Case 3 This fetus was delivered to a 30 year old gravida 4,

para 1, abortus 2 mother. An ultrasound examination at 20 weeks of gestation showed short limbs with curv- ing of the long bones. A second ultrasound study per- formed at 21 weeks demonstrated shortness of the long bones which were in the lowest fifth centile. This was associated with curvature and thickness of the right

Fig. 1. Case 2. 23V7-week-old fetus showing marked micromelia of all extremities. The typical hitchhiker thumbs and clubfeet are evident.

femur and the left tibia, hitchhiker thumbs, and clubfeet, resulting in a diagnosis of DD. There was no family history of osteochondrodysplasia. After counsel- ing, the parents opted for termination of the pregnancy.

RADIOLOGICAL EXAMINATION All three cases showed similar radiological findings

(Fig. 2). The long bones were moderately short with slight inward bowing. The metaphyses of all long bones were broad but were most prominent in the femora. The vertebral bodies appeared to be of normal width without platyspondyly. Scoliosis was not evident in any of the cases. The ribs were normal. The typical abduc- tion of the thumbs, or hitchhiker thumbs, was readily seen in the radiographs. The small bones of the hands were normal in cases 1 and 3 but showed mild variation in size in case 2. The ilia were normal in configuration when compared with controls.

PATHOLOGICAL EXAMINATION Grossly, the femoral shaft was short and thick with

broad metaphyseal ends. Histopathologically all three cases showed similar changes, which were seen pri- marily in the resting cartilage. At low magnification the changes appeared as irregular myxoid degenera- tion with small cystic areas (Figs. 3,4). At higher mag- nification, the chondrocytes were surrounded by a halo of dense appearing cartilage matrix. The chondrocytic nuclei were larger than normal with some of the lacu- nae containing two nuclei. The physeal growth zone showed normal appearing hypertrophic and proliferat- ing zones with normal columnization. In rare foci, the cystic change appeared to encroach on the proliferating zone. The degenerative changes described above were seen in the vertebral bodies and in the tracheal carti- lage. Alcian blue and trichrome stains showed a similar intensity of staining in both the chondrocyte cytoplasm and in the dense halo. The myxoid areas did not stain with alcian blue, suggesting that these are degenera- tive changes. All the special stains tended to delineate the lesions better.

DISCUSSION The histopathologic characteristics of DD in newborn

infants and older patients are well defined. Rimoin [1975] and Sillence et al. [1979] have shown that rest- ing cartilage from all sites is distinctly abnormal. The

302 Qureshi et al.

Fig. 2. Xeroradiograph of the fetus in Case 1. All long bones are shortened and show prominent metaphyseal flaring. The small bones of the hands and feet auuear normal. No DlatvsDonddv is seen. The

Fig. 3. Low magnification of the epiphyseal cartilage in DD show- ing the myxoid degeneration with cystic changes in the resting carti- lage. ~~ The hypertrophic and proliferative zones appear normal with good columnization. L 1 - ” - - I

ilia are normal in configuration.

chondrocytes are larger than normal and are irregu- larly distributed in the surrounding densely staining blue matrix. They also appear to be irregularly distrib- uted within the lacunae which may contain 3-4 nuclei as compared to the normal 1-2 nuclei. Scattered foci are acellular and within these foci residual thickened collagen fibers form an irregular lacy pattern within amorphous material. We noted histopathologic changes similar to those described above in the resting cartilage in all three of the second trimester fetuses. Cystic changes similar to those seen in the long bones are also seen in the pinna, larynx, and costal cartilage. These changes were identified by Freedman et al. [19741 in the tracheal cartilage of a neonate with DD who died of respiratory distress and were also noted in the tracheal cartilages of two of the three DD fetuses in this study.

The differential diagnosis of DD includes pseudodi- astrophic dwarfism [Burgio et al., 1974; Eteson et al., 1986; Spranger and Maroteaux, 19901 and atelosteoge- nesis (AO) type I1 [Sillence et al., 19871, in which there is shortness of the limbs associated with cervical scolio- sis and abnormalities of the digits. Patients with pseu-

dodiastrophic dysplasia typically have a large cranium with midface hypoplasia, small chin, cleft palate, rhi- zomelic shortness of the limbs, hitchhiker thumbs, characteristic interphalangeal joint dislocations, platyspondyly, and progressive scoliosis. Additional ra- diological findings include hypoplasia of the inferior ilia, a clublike expansion of the proximal femora, and a short first metacarpal. Histopathologic findings typi- cally include irregular columnization of the cartilage cells, short, widely separated, irregular primary tra- beculae, and normal-appearing resting cartilage. In contrast, DD shows no platyspondyly or interpha- langeal dislocations. The resting cartilage shows ab- normal myxoid degeneration with cystic change, with larger than normal chondrocytes and a normal physeal growth zone is usual.

Sillence et al. [19871 reported four cases of a neonatal “diastrophic-like’’ dysplasia which they called A 0 type 11, because it was similar to, yet distinct from, A 0 (later designated A0 type I) as previously described [Maroteaux et al., 19821. The radiological findings in- cluded marked shortness of the long bones with meta-

Diastrophic Dysplasia 303

In conclusion, although sonographic resolution has allowed more extensive evaluation of fetuses with os- teochondrodysplasias, careful autopsy studies includ- ing detailed radiologic and histopathologic examination of the cartilage and physeal growth zone remain essen- tial for proper diagnosis. Further molecular biologic studies will help identify “families” of osteochondrodys- plasias and allow for appropriate genetic counseling of the family.

Fig. 4. Higher magnification of the resting cartilage. The chondro- cytes are surrounded by a dark rim of cartilaginous matrix. Myxoid degeneration with delicate fibrils adjacent to the cystic areas can be seen.

physeal widening, characteristic bifid humerus and a rounded distal femur, and severe dysplastic-hypoplastic changes of the bones of the hands and feet. Marked cer- vical kyphosis with dysplastic changes, a V-shaped lum- bosacral canal, and slight platyspondyly. The iliac bones were almost round with irregular outlines of the iliac crests. These changes are similar to those seen in DD, but with more severe involvement of the small tubular bones of the hands and feet and the vertebral bodies. Histopathologically, the resting cartilage in A 0 type I1 was extremely abnormal with dense perilacunar staining and many cystic areas caused by attenuation of the reserve zone matrix. Many of the cystic areas con- tained only radiating threads of fibers. Chondrocyte nu- clei appeared rounded and primitive. The appearance of the resting cartilage in DD is similar to that observed in A 0 type 11. Another case of A0 type I1 with histopatho- logic findings similar to those seen in DD was reported by Nores et al. [19921. ?tyo previous cases reported by McAlister et al. [19851 were considered to be A0 type I1 by Sillence et al. [19871, although Spranger and Maroteaux [ 19901 thought that these cases represented a distinct entity. The similarities between A 0 type I1 and DD suggest the possibility that these are variants of the same disease rather than separate entities with A 0 type I1 being the more severe or lethal form and classic DD the milder form of the disease.

Recently, Hastbacka et al. [19941 have identified the DD gene, which encodes for a sulfate transporter and is located on distal chromosome 5q. It is possible that other bone dysplasias may also show a defect in sulfate metabolism, suggesting a possible pathogenetic rela- tionship to DD. Such a relationship has been suggested by Spranger [19881, who included A0 I1 and McAlister dysplasia, pseudodiastrophic dysplasia, and de la Chapelle dysplasia as members of the DD “family.”

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