Morphologic studies in the skeletal dysplasias.

REVIEW ARTICLE MORPHOLOGIC STUDIES IN THE SKELETAL DYSPLASIAS

MORPHOLOGIC STUDIES IN THE SKELETAL DYSPLASIAS Nomenclature and Classification

814

Clinical and Genetic Findings

815

Radiologic Findings

815

Biochemical Diagnosis

816

Processing Growth-Plate Specimens for Morphologic Studies

816

Histologic Characteristics and Ultrastructure of Growth-Plate Cartilage

818

Morphologic Findings in Chondro-osseous Tissues in the Skeletal Dysplasias

820

Skeletal Dysplasias Identifiable at Birth

821

Achondrogenesis Achondrogenesis I (Parenti-Fraccaro) Achondrogenesis II (Larger-Saldino) Thanatophoric Dvsplasia Thanatophoric Dvsplasia With Cloverleaf Skull Deformity Short-Rib-Polydactyly Syndromes Short-Rib-Polydactyly Dysplasia I (SaldinoNoonan) Short- Rib-Polydactyly Dysplasia II (Majewski) Chondrodysplasia Punctata Rhizomelic Chondrodysplasia Punctata Conradi-HUlnermann Chondrodysplasia Punctata Sex-Linked Chondrodysplasia Punctata Campomelic Dysplasias Long-Limbed Campomelic Dysplasia Short-Limnbed Campomelic Dysplasia, Normocephalic Type Short-Limbed Campomelic Dysplasia With Craniosynostosis Achondroplasia Homozygous Achondroplasia Diastrophic Dysplasia Metatropic Dysplasia Chondroctodermal Dysplasia (Ellis-van Creveld Syndrome) Asphyxiating Thoracic Dysplasia

Spondyloepiphyseal Dysplasias Kniest Dysplasia

Mesomelic Dysplasias Aeromesomelic Dysplasias Skeletal Dysplasias Indentifiable in Later Life Hypochondroplasia Dyschondrosteosis Metaphyseal Dysplasia Spondylometaphyseal Dysplasias Multiple Epiphyseal Dysplasias Arthro-ophthalmopathy (Stickler) Pseudoachondroplasia Spondyloepiphyseal Dysplasia Tarda Spondyloepiphyseal Dysplasia, Other Forms Dyggve-Melchior-Clausen Syndrome Spondyloepimetaphyeal Dysplasias Myotonic Chondrodysplasia (Catel-Schwartz-Jampel) Parastremmatic Dysplasia Trichorhinophalangeal Dysplasias Conclusion

821 821 822 823 824 824 824 825 825 826 826 827 827 827 828 828 828 829 830 831 831 832 833 833 834 834

835 835 835 835 837 837 838 838 839 840 840 840 841 841 841

841

Morphologic Studies in the Skeletal Dysplasias A Review D. 0. Sillence, MD, W. A. Horton, MD, and D. L. Rimoin MD, PhD

Considerable progress has been made in the delineation of the genetic skeletal dysplasias, a heterogeneous group of disorders that consist of over 80 distinct conditions. Morphologic studies have added a further dimension to the delineation of these conditions, their diagnosis, and the investigation of their pathogenetic mechanisms. In certain diseases, the morphologic alterations are characteristic and pathognomonic. In others only nonspecific alterations are observed, whereas in still other disorders growth-plate structure is essentially normal. Histologic, histochemical, and electronmicroscopic studies of growth-plate cartilage have provided new insights into the complexity of morphogenetic events in normal growth through the demonstration of morphologic defects in the genetic disorders of skeletal growth. As yet, very little is known of the biochemical abnormalities underlying the morphologic abnormalities. However, the great variety of morphologic findings points to a number of different pathogenetic defects in the synthesis, release, and assembly of connective tissue macromolecules and in the cells involved in growth-plate metabolism. (Am J Pathol 96:811-870, 1979)

THE HUMAN SKELETAL DYSPLASIAS are a heterogeneous group of heritable connective-tissue disorders associated with abnormalities in the size and shape of the limbs, trunk, and/or skull that frequently result in disproportionate short stature. In recent years it has become apparent that these comprise over 80 distinct conditions that can be distinguished on clinical and radiologic grounds.1 (See Appendix.) Morphologic studies have further defined the heterogeneity and have provided valuable insight into the variety of the pathogenetic mechanisms producing them. It has been 15 years since Rubin 2 published his classic monograph on the classification of bone dysplasias. This paper brought together many clinical, radiologic, morphologic, and experimental observations regarding normal and abnormal skeletal growth. The skeletal dysplasias were interpreted as disorders of normal bone growth or remodeling and were classified by the potential site of the anatomic defect in the skeleton, eg, From the Division of Medical Genetics, UCLA School of Medicine, UCLA-Harbor Medical Center, Torrance, California, and the Department of Metabolism, Endocrinology, and Genetics, University of Kansas Medical Center, Kansas City, Kansas. Supported in part by US Public Health Service Grants HD-11966, GM-07414, and RR-00425; a research grant from the National Foundation of the March of Dimes (I-280); a Basil O'Connor Starter Grant (5-149); and a grant from the Human Growth Foundation. Accepted for publication May 11, 1979. Address reprint requests to David L. Rimoin, MD, Professor of Pediatrics, Chief, Division of Medical Genetics, UCLA School of Medicine, Harbor General Hospital Campus, 1000 West Carson Street, Torrance, CA 90509. 0002-9440/79/0910-081 1$01.00 813 © American Association of Pathologists

814

SILLENCE ET AL

American Journal of Pathology

epiphyseal, metaphyseal, and diaphyseal dysplasias. This interpretation has had a major impact on the description and further delineation of disorders of skeletal growth. Numerous new disorders have been defined,3-27 and the nomenclature, classification, and morphologic findings in these dysplasias are the subject of this review. Nomenclature and Classification

The rapid growth in knowledge has resulted in a complex new terminology. Two international meetings have been held, the first in 1969,283o the second in 1977,1 to formulate an acceptable nomenclature for constitutional disorders of bone. The revised nomenclature will be used during this review. (See Appendix.) It is based entirely on the clinical, genetic, and radiographic characteristics of each of the dysplasias. Further delineation of these conditions has occurred when specific morphologic and biochemical defects have been demonstrated. Eventually a classification based on fundamental biochemical abnormalities will be possible. The second international nomenclature divides the skeletal dysplasias into five major groups: osteochondrodysplasias, ie, abnormalities of cartilage and/or bone growth and development; dysostoses, ie, malformations of individual bones, singly or in combination; idiopathic osteolyses, ie, conditions associated with resorption of bone and with secondary abnormalities; chromosomal aberrations with unusual skeletal abnormalities; and primary metabolic abnormalities, a large group of conditions where the pathogenetic mechanism is known or a biochemical defect has been demonstrated. The specific names of the majority of disorders have been retained, but certain terms were changed to conform with the distinction between dysplasias, ie, disorders of growth, and dysostoses, ie, malformations of the skeleton, singly or in combination. For example, metaphyseal dysostoses was changed to metaphyseal chondrodysplasias. The terms dwarfism and nanisme were replaced by dysplasia or dysplasie, because this word can be translated universally, eg, thanatophoric dwarfism is to be called thanatophoric dysplasia. The terminology for many of the dysplasias has been based upon that part of the skeleton that is affected in radiographs. Thus, dysplasias which demonstrate significant epiphyseal, metaphyseal, or diaphyseal abnormalities are called epiphyseal, metaphyseal, or diaphyseal dysplasias, respectively. Some dysplasias are named for the segment of the limbs that shows the shortening, eg, rhizomelic (proximal), mesomelic (middle), and acromelic (distal) dysplasias. Where the spine is involved, the prefix spondylois used, eg, spondyloepiphyseal dysplasias. Where the skull is involved, the prefix cranio- is used, eg, craniometaphyseal dysplasia. Other dys-

Vol. 96, No. 3 September 1979

SKELETAL DYSPLASIAS

815

plasias are named for a combination of these features, eg, spondylometaphyseal dysplasia, acromesomelic dysplasia. Still others are designated by a Greek term that describes the appearance of the bone or the course of the disease, eg, diastrophic (twisted) dysplasia, thanatophoric (deathseeking) dysplasia, and metatropic (changing) dysplasia. There are a few conditions where a descriptive term is used based on concepts of pathogenesis, eg, achondroplasia, ie, absence of cartilage growth. In this case the terminology is a misnomer, as cartilage does form at the growing ends of the long bones in achondroplasts but is reduced in amount. This review is concerned primarily with those disorders listed as osteochondrodysplasias showing defects of growth of tubular bones and/or the spine, ie, the chondrodystrophies. These will be discussed in the order presented in the international classification. Before discussing specific conditions, we have reviewed the approach to obtaining the clinical, radiologic and morphologic data necessary for accurate diagnosis. Clinical and Genetic Findings

Broad distinctions can be made between groups of patients based on clinical characteristics, ie, the age of presentation, whether the condition is lethal in the newborn period, the occurrence of associated nonskeletal features, and on the natural history of the skeletal and nonskeletal manifestations throughout life. Careful physical examination may lead to diagnosis in some cases. The family history in every case is obligatory. Certain conditions may be defined clearly by their inheritance pattern, eg, x-linked recessive spondyloepiphyseal dysplasia tarda may be diagnosed definitively on genetic grounds. Furthermore, the observation of a particular inheritance pattern may lead to the definition of a new condition. In this regard, an xlinked variety of chondrodysplasia punctata has recently been distinguished from the more common dominantly inherited variety. 117 Radiologic Findings

The present nomenclature and distinction between various dysplasias are largely based on radiographic findings. Therefore, a full skeletal survey, examined by an investigator skilled in the diagnosis of the skeletal dysplasias, is essential. This applies just as well to newborns with lethal dysplasias as to infant patients in whom serial radiographs may need to be examined before a final radiologic diagnosis can be reached. A skeletal survey should include the following views: anteroposterior and lateral views of the skull; anteroposterior and lateral views of the spine; antero-

816

SILLENCE ET AL


posterior views of the upper limbs, including hands; anteroposterior and lateral views of the chest; an anteroposterior view of the pelvis; an anteroposterior view of the lower limbs; and a lateral view of at least one ankle. The clinical, genetic, and radiographic findings in a particular case can be assessed against the background of original papers 3-27 and recent literature 31-39 on the skeletal dysplasias. Because of the rapid proliferation of knowledge of these disorders, the opinion of someone active in this field may be very valuable in establishing a diagnosis. Biochemical Diagnosis

There are some skeletal dysplasias in which a biochemical abnormality has been found 40-44 but the basic defect in an enzyme or structural protein has not yet been established. In hypophosphatasia (several forms) there is clearly a defect in bone alkaline phosphatase activity.45'46 However, the precise defect in the enzyme is not known.46 In thanatophoric dysplasia, electrophoretic variants have been identified among the cartilage collagens.40 Furthermore, biochemical studies of thanatophoric-like skeletal dysplasias show distinct cartilage collagen electrophoretic variants that indicate that there is further heterogeneity in this group of newborns.47 In Kniest dysplasias, some patients studied have demonstrated an abnormal pattern of excretion of urinary glycosaminoglycans (GAGS).43 These patients have shown a slightly elevated excretion of total GAGS and a disproportionately elevated excretion of keratan sulfate.41 The pattern of GAGS has also been studied in patients with pseudoachondroplasia.42'44 Processing Growth-Plate Specimens for Morphologic Studies

Processing methods involving formalin fixation and paraffin embedding following decalcification of the tissues have been extensively used. We had routinely stained such sections with hematoxylin and eosin, Masson's trichrome, and alcian blue/periodic-acid-Schiff (PAS). In the past 3 years, however, we have found that for studying chondroosseous tissues, plastic embedding offers many advantages over paraffin embedding.48-51 For example, calcification can be studied, since decalcification is not necessary. In addition, plastic embedding in general provides much better preservation of both morphologic and chemical integrity of the tissue. Moreover, glycol methacrylate, the plastic we have employed, is water-miscible, so that water-soluble stains, enzymes, substrates, and so forth, can be used, providing histochemical information. We now use plastic embedding for the majority of studies. On occasion we have used a short decalcification


SKELETAL DYSPLASIAS

817

followed by plastic embedding. Our studies have been based on autopsy or, preferably, biopsy specimens of the costochondral junction and iliac crest, which have been divided into small portions, each about 2 mm thick and processed for histologic studies, histochemical studies, and electron microscopy.

For electron microscopy, specimens are fixed in a modified Karnovsky's fixative (glutaraldehyde, 2.5%, paraformaldehyde, 2.5%, and 0.1 M cacodylate buffer, pH 7.4, or glutaraldehyde, 2.5%, in 0.1 M buffer).5253 The block of tissue is cut immediately into small slices measuring approximately 0.5-1 mm by 0.5-1 mm by 2-3 mm, with the long axis perpendicular to the growth plate, while immersed in fixative. These tiny blocks are then fixed for 2 hours in the primary fixative. Subsequent processing includes osmium postfixation, dehydration in graded acetone, and embedding in Spurr's low-viscosity resin, hard mixture.54 Several portions are processed for light microscopy. The specimens are dehydrated and infiltrated in increasing concentrations of GMA, 50%, 75%, 90%, and 100%, in distilled water. We have found that uniform polymerization of the blocks can be obtained by doubling the recommended concentration of the catalyst (benzoyl peroxide) in the final infiltration prior to polymerization with the addition of the activator (Solution B, Polysciences).55 Fixation, infiltration, and polymerization are all done at 4 C. Sections 1-3 ,u in length can be cut with a ½/2-inch glass knife on a JB-4 microtome (Sorvall), placed in water and immediately floated onto slides that are placed upright to dry in a refrigerator at 4 C. We carry out the staining by placing the slides directly into the staining solutions; the plastic is not removed. Following the staining procedure, the slides are rinsed in running water briefly and blown dry with a blast of cool air. The sections are mounted in Permount (except for oil red 0 stain, which is mounted in glycerin). Sequential sections of each specimen are stained with a series of techniques designed to show form and structure and to identify specific growth-plate substances. In most cases the techniques employed here have been modified from existing staining methods. To study morphologic aspects, osmium-postfixed sections are stained by Wyrick's silver method 48 and nonosmium-fixed sections by Stains All.56 The former technique shows the intracellular structures well, the latter matrix structure. Nonosmium-fixed sections are employed for histochemical studies. To evaluate the distribution of proteoglycan and the type of bound glycosaminoglycans, sections are stained with 0.1 % alcian blue in 0.45 M and 0.9 M MgCI2 57,58 as well as following digestion with 0.1 % bovine testicular hyaluronidase 59 and counterstained with basic fuchsin. The two major

818

SILLENCE ET AL


types of cartilage glycosaminoglycan, chondroitin sulfate and keratan sulfate, are thought to stain at 0.45 M MgC92, but keratan sulfate only when the magnesium chloride concentration is raised to 0.9 M or after hyaluronidase digestion.57'58 Calcification of cartilage (provisional calcification) and bone is assessed by the standard Von Kossa (AgNO3) method.60 The aniline blue component of a modified Masson's trichrome stain is used to identify collagen.61 In addition, cartilage matrix collagen can be stained by a modified silver methenamine method.62 Lipids are studied by oil red 0 staining.63 In biopsy specimens, the activity of the enzymes alkaline phosphatase 64 and acid phosphatase 65 can be assessed. Histologic Characteristics and Ultrastructure of Growth-Plate Cartilage

Endochondral (growth-plate) ossification, ie, ossification occurring from the growing ends of bones, can be found in many sites throughout the body, not just at the ends of the long bones. In every area where this is found, it is observed to be a highly organized sequential transformation of cartilage into trabecular bone. The sequence in all areas is the same, although in some areas of the skeleton, eg, the iliac crest, the sequence is foreshortened, whereas in others it is characteristically prolonged, eg, costochrondral junction.291 The cartilage zones that are observed are described as 1) reserve, or resting, cartilage; 2) proliferative cartilage. or the zone of flattened chondrocytes; 3) the zone of hypertrophic and degenerative chondrocytes; and 4) the zone of chondro-osseous transformation showing vascular invasion, calcified cartilage resorption, and trabecular bone formation (metaphysis) (Figure LA). The reserve cartilage is characterized histologically by a random arrangement of chondrocytes.291 In the fetus and young child, before ossification of the ends of the bones (epiphyses), the reserve zone is greatly expanded. The costal cartilage and iliac crest and the cartilage precursors of mnany areas of the fetal skeleton consist of reserve cartilage. In these areas the chondrocytes are relatively plump. A small proportion may contain one or more vacuoles and an occasional lipid droplet. Seen with the electron microscope (Figure 1 B), the Golgi apparatus appears well marked. The rough endoplasmic reticulum may be clearly present but not unduly prominent. There are a few mitochondria and some scattered pockets of glycogen arranged around the nucleus. A perichondrocyte lacunar space is present but is narrow, compared with cells in other zones. Within a few millimeters of the zone of chondro-osseous transformation, a dramatic change appears in the organization of the chondrocytes.29 They become arranged in parallel rows, become flattened in appearance, and are separated by both longitudinal and horizontal septums (Figure


SKELETAL DYSPLASIAS

819

1C). Ultrastructurally these cells show an increased amount of cytoplasmic glycogen; toward the metaphysis, the rough endoplasmic reticulum becomes more prominent. The Golgi apparatus is often well marked. Around these cells the lacunar region appears wide; it may contain beaded string-like material or large droplets of electron-dense material when the tissue has been processed by standard aldehyde/osmium fixation and uranyl acetate block staining (Figure 1D). However, when the tissue is processed using ruthenium red, alcian blue, or safranin 0, this lacunar region can be seen to be completely occupied by specific ptoteoglycans. Outside the lacunar region the matrix takes on a more fbrous appearance in tissue fixed by the standard methods. Within several cell diameters of the zone of transformation these flattened chondrocytes give way to the hypertrophic and degenerative cell zone. In the hypertrophic cell zone the lacunas are greatly enlarged (Figure 2A). In conventional histologic sections the chondrocytes appear shrunken and attenuated and the lacunas grossly expanded. Many of these cells appear degenerative (and this zone is often described as the zone of degenerative chondrocytes). However, in well-fixed light in electronmicroscopic sections it can be seen that many of these cells are not actually degenerated but morphologically very different from proliferative chondrocytes (Figure 2B). It is characteristic of these cells that the rough endoplasmic reticulum becomes very prominent and may occupy the greater part of he hypertrophic cell cytoplasm. The lacunas, moreover, are prominent and show masses of small electron-dense droplets. Beyond the lacunas the matrix appears fibrous and there is a definite longitudinal orientation of the collagen fibers perpendicular to the zone of chondro-osseous transformation. It has been argued that many of the degenerative features described in these cells are the result of artifacts of fixation involving osmotic effects and structural changes in tissues easily damaged by anoxic insult.66 Matrix vesicles, a prominent feature of the zones of proliferative and hypertrophic chondrocytes, are scattered electron-dense membranebound vesicles that are believed to be involved with crystal nucleation and the process of calcification.67 However, these vesicles are also seen around chondrocytes in reserve cartilage.68 Therefore, the ultrastructural appearance of matrix vesicles is not necessarily an indication of imminent calcification in any region. hlowever, the matrix vesicles of the hypertrophic zone may well be specialized for enhancing the concentration of calcium or phosphate and contributing to the local events that lead to crystal nucleation. In the zone of chondro-osseous transformation, the horizontal septums

820

SILLENCE ET AL


between hypertrophic chondrocytes are broken down by a process presumably involving cellular and local enzymatic factors. Eventually there is penetration by metaphyseal vascular tissue into ruptured lacunas (vascular invasion), leaving only heavily calcified longitudinal trabeculas of cartilage matrix, which serve as primary osteoid trabeculas. Within the zone of trabecular bone formation, bone is laid down, and within 0.5-1 cm of the zone of transformation these cartilage trabeculas are resorbed and replaced by bone. In the human fetus and newborn the growth plate in most areas of the skeleton is continuous with and undifferentiated from the cartilaginous epiphysis. With the appearance of ossification of the epiphyseal centers, the growth plate of the long bones is sandwiched between epiphyses (or articular ends of the bones) and diaphyses (or shafts of the bones). The timing of the ossification of the epiphyses in prenatal and postnatal life is age-related and shows considerable consistency within the human species 292-294

During adolescence the growth plates undergo involution, and the epiphyses fuse with the diaphyses. During this period the growth plate is characterized by relative hypocellularity, progressive shortening of the columns of proliferative cells, a rounding up of the cells in clusters, and changes in the matrix, which develops a more fibrous texture.295 A secondary ossification center appears in the iliac crest. The costochondral junction, however, does not disappear at adolescence but remains into adult life. The columns of proliferative chondrocytes are markedly reduced in length, and there is a clustering of cells. In the fifth and sixth decades, the costal cartilages show progressive focal calcification (chondrocalcinosis). Studies of the iliac crest and the costochondral junction in both normal and diseased tissues have shown that the sequence of morphogenetic changes at various ages is identical to that observed in the growth plate of the long tubular bones. Because biopsies of the iliac crest and the costochondral junction are more readily done in human beings, these are the most studied of the growth areas of the skeleton in the human skeletal dysplasias. Morphologic Findings in Chondro-osseous Tissues in the Skeletal Dysplasias The morphologic abnormalities observed by various groups working with the skeletal dysplasias have been summarized in a number of recent publications.35-37,69-78 In such a rapidly expanding field of knowledge it is inevitable that there is not total agreement on some findings. We will attempt to draw attention to these differences in observations and interpretation where they


SKELETAL DYSPLASIAS

821

occur. Similarly, a wide range of terminology has been used to describe growth-plate abnormalities. We will also attempt to standardize this terminology as much as possible. Skeletal Dysplasias Identifiable at Birth

Achondrogenesis

In the latest classification only two syndromes, achondrogenesis I (Parenti-Fraccaro) and achondrogenesis II (Langer-Saldino), have this designation. They are characterized by severe prenatal growth failure with stillbirth or early neonatal death. Both trunk and limbs are very short. Radiographically they show a defect in ossification of the vertebral bodies, pelvis, skull, and long bones.35 Both syndromes are inherited in an autosomal recessive fashion. Much confusion has arisen because of the numeric subdivision used by various authors in the past. A recent publication has proposed that there are four varieties of achondrogenesis.8' However, further clinical, radiologic, and morphologic data will be required to prove whether there are more than the two classic disorders. A nonlethal form of short-limbed dwarfism described by Grebe 79 and subsequently in a large Brazilian family by Quelce-Salgado 80 had been called achondrogenesis Type I1,21 but this disease bears little resemblance to the two forms of lethal achondrogenesis and should be described as Grebe dysplasia.35 Achondrogenesis I (Parenti-Fraccaro). In addition to the original reports, clinical and radiographic findings have been reported by a number of authors.69'78'84-88 In contrast to the Langer-Saldino type of achondrogenesis, the head does not appear significantly large compared to the trunk. On the other hand, the skull may be extremely soft and appear to consist of small islands of bone in a membranous calvarium. The radiographic findings are diagnostic, showing poorly ossified membranous bones in the skull; thin ribs, which are frequently fractured; a total absence of ossification of vertebral bodies; and small, square long bones with many spurs.35'37'38'69 Congenital heart defects were observed in three patients autopsied and consisted of patent ductus arteriosus, ventricular septal defect, and patent foramen ovale.69 Pathologic changes in the skeleton have been described by a number of authors.S9,78,84,8890 We have studied 4 patients. The growth plate in all cases has shown a severe disturbance in endochondral ossification (Figure 2C). All zones of the growth plate were densely hypercellular. Reserve zone chondrocytes were slightly enlarged and vacuolated, containing

822

SILLENCE ET AL


PAS-positive inclusion bodies 89 (Figure 2D). The normal progression of chondrocytes was lost, although some increased hypertrophy appeared in cells adjacent to the metaphysis. Calcification of cartilage and trabecular formation were very disorderly, with irregular capillary penetration and little column formation. The inclusion bodies seen in reserve-zone chondrocytes were observed less frequently in proliferative chondrocytes.89 No osseous or hemopoietic tissue was found in the cartilagenous sternum or vertebral bodies.89'78'86 Endochondral ossification has been examined by scanning electron microscopy 90 and showed diminished width of the longitudinal septums which are normally found between hypertrophic chondrocytes. The calcifying matrix vesicles, which are the sites of initial calcification in cartilage, were abnormally large.90 Achondrogenesis II (Langer-Saldino). In this type of achondrogenesis, the head is large in relation to the rest of the body. Both the trunk and limbs are shortened and the trunk has a squared appearance. The abdomen is distended, and fetal hydrops is frequently present.83587'88'91-93 The radiographic features are diagnostic, with marked underossification of the vertebral bodies, sacrum, pubis, and ischium. The long bones are shortened but not as severely as in achondrogenesis I. The metaphyseal margins are irregular, with bony spurs, and give a cupped appearance to both ends of the bones. The ribs are short, with absent sternal ossification.38 Chondro-osseous tissue in Langer-Saldino achondrogenesis differs markedly from that of any other chondrodystrophy.71'78'88 We have studied 3 cases.85'7' On gross inspection the epiphyseal cartilage appears lobulated and mushroomed, with increased vascularity. Reserve cartilage from all sites examined was markedly hypercellular, consisting primarily of large, ballooned chondrocytes with little intervening matrix (Figure 3A). The amount of intercellular matrix appeared to be least in the region of those chondrocytes surrounding vascular areas of the cartilage. At the growth plate, this hypercellularity resulted in an absence of cellular column formation with complete disorganization of endochondral ossification (Figure 3B). Vascular invasion of the hypercellular cartilage occurred at irregular intervals, producing spicules consisting of degenerative chondrocytes surrounded by calcified cartilage. The primary trabeculas were decreased in number and irregular in size, and some were oriented horizontally. There was relative overgrowth of membranous bone, resulting in the cupping of the epiphyseal cartilage, seen radiographically as cupped metaphyses. The vertebrae consisted almost entirely of this hypercellular cartilage, with only a small area of ossification within the vertebral body.


SKELETAL DYSPLASIAS

823

Thanatophoric Dysplasia

This newborn dysplasia is characterized by markedly shortened extremities, a trunk of relatively normal length, and a relatively large head showing craniofacial disproportion. It was delineated in 1967 by Maroteaux and colleagues 15 and named from the Greek thanatos (death) and phorus (seeking). These infants tend to be stillborn or die from respiratory distress in the newborn period. The thorax is very narrow in all dimensions and pear-shaped. Severe hydrocephalus may occur and complicate delivery of the baby. A variety of extraskeletal malformations have been described in patients with thanatophoric dysplasia.8r These include patent ductus arteriosus, atrial-septal defects, coarctation of the aorta, absence of the corpus callosum, cerebral and cerebellar microgyri, temporal-lobe abnormalities, and herniation of the cerebellum.94-97 The cloverleaf skull anomaly (Kleeblattschidel syndrome) has been described in association with thanatophoric dysplasia. This will be discussed below. The radiographic findings in thanatophoric dysplasia are diagnostic.85'88'47 Characteristically on frontal projection the lumbar vertebrae have an inverted U appearance while marked platyspondyly, with narrowing of the midportion of the vertebral bodies, is seen on lateral view. The femurs are curved, with medial and lateral spikes at the lower end. The ribs are short and flared and cupped anteriorly. The inheritance of thanatophoric dysplasia is not known. The present evidence suggests that it most likely arises from a new dominant mutation, since the great majority of cases have been sporadic. Some authors have stated that thanatophoric dysplasia is inherited in an autosomal recessive manner. However, their conclusions were based upon reports of infants 98-101 who, upon further review, were found to have other recessively inherited skeletal dysplasias such as achondrogenesis I or II. One set of affected siblings with normal parents has been reported,70 but in view of the fact that all other cases have had a negative family history, this is not sufficient evidence to indicate autosomal recessive inheritance. Chondro-osseous histologic abnormalities in thanatophoric dysplasia are seen as relatively normal resting cartilage with generalized disruption of endochondral ossification 65,47,70-74 (Figure 3C). The resting cartilage shows round to spindle-shaped chondrocytes in an abundant homogeneousstaining matrix. The growth plate is disrupted. In most areas there is no column formation and no orderly progression of chondrocyte evolution. In some areas there is a generalized increase in the size of the chondrocytes, resulting in scattered hypertrophic cells with no column formation. Along the growth plate of most bones one can find small areas of fairly regular columnar alignment of hypertrophic cells. However, the surrounding

824

SILLENCE ET AL


cellular matrix stains more intensely than normal. Vascular invasion of the growth plate occurs at irregular intervals, resulting in an irregular array of short, blunt, and broad spicules of calcified cartilage and bone. In some areas these aggregate in a lattice-like formation, resulting in horizontally aligned trabeculas. Thanatophoric Dysplasia With Cloverleaf Skull Deformity. The cloverleaf skull, or Kleeblattsch'adel, is a grotesque trilobe deformity due to fused coronal and lambdoid sutures. Hydrocephalus is present, and the cranial fossae are much enlarged and displaced downwards. The association of thanatophoric dysplasia with cloverleaf skull deformity has been reported in a number of cases.102-108 Cloverleaf skull deformity may also occur as an isolated skeletal anomaly or in association with other minor skeletal abnormalities. 106 Apart from the Derby siblings reported by Partington,106 all cases of thanatophoric dysplasia with Kleeblattschadel have been sporadic. Although it is possible that the mode of inheritance may be autosomal recessive, other genetic mechanisms could account for the above observation. We have studied two patients with thanatophoric dysplasia with Kleeblattschadel deformity. The growth plate in each case showed many similarities to typical cases of thanatophoric dysplasia. However, the growth plates of the long bones showed considerably more areas where the cells had a fibroblastic appearance and the matrix a fibrous appearance, and bone was deposited directly on a hypercellular matrix 47 (Figure 3D). Short-Rib-Polydactyly Syndromes

This classification includes a number of lethal neonatal skeletal dysplasias associated with severe narrowing of the chest, short limbs, polydactyly, and a variety of other associated abnormalities. At least two syndromes can be delineated,26'38 and a third is probable.111 113 These infants have all been stillborn or died in the newborn period and commonly had a protuberant abdomen and hydropic appearance at birth. The short-rib polydactyly syndomes must be distinguished from asphyxiating thoracic dysplasia and chondroectodermal dysplasia. They are inherited in an autosomal recessive fashion.26'109'110 Short-Rib-Polydactyly Dysplasia I (Saldino-Noonan). These infants have also shown a variety of congenital anomalies. They include transposition of the great vessels, polycystic kidneys, hypoplastic lungs, anal atresia, and anomalies of the esophagus and genitourinary tract.26 Radiologically they show very short horizontally oriented ribs and short limb


SKELETAL DYSPLASIAS

825

bones with pointed ends and spikes at the borders of the metaphyses.38,114-116 There are some differences between the radiologic appearance of cases reported by Saldino and Noonan 109 and other authors.26'110 However, Spranger and colleagues 38 argue that the more severe ossification defect in the siblings reported by Saldino and Noonan 109 probably reflected the prematurity of those infants, compared with other cases in the literature. If such is the case, then other newborns reported to be different from the Saldino-Noonan babies are likely to have the same lethal dysplasia. 111,112 Chondro-osseous tissue abnormalities have been reported in 2 patients,26 and we have studied 2 further cases. There was disorganized proliferative and hypertrophic cartilage with reduced numbers of chondrocytes and disorganized columns. The formation of trabecular bone was grossly abnormal, with broad stumpy primary trabeculas (Figure 4A). The zone of chondro-osseous transformation was irregular, with tongues of cartilage extending into the metaphysis and trabeculas of newly formed bone extending into the cartilage, corresponding to the ragged radiologic appearance of the metaphysis. Ultrastructural studies in one case showed relatively normal chondrocyte structure.26 The matrix was quite abnormal, with fibril disorganization, abnormal fibrils with tapered ends, and abnormal amounts of mature collagen.26 Short-Rib-Polydactyly Dysplasia II (Majewski). Infants with SRP II may have both pre- and postaxial polysyndactyly 26,110 and commonly have cleft upper lip or palate and low-set ears. Associated malformations have included patent ductus arteriosus; cystic dysplastic kidneys; hypoplastic epiglottis, larynx, and lungs; and intestinal malrotation.26 Radiographically they have shown short horizontally oriented ribs, premature epiphyseal ossification, very short limbs, and pre- or postaxial polydactyly of hands and feet. The tibias are characteristically shortened proximally, with rounded contours.35638 Chondro-osseous tissue studies show irregular columnization at the growth plate.26 Chondrodysplasia Punctata

This term encompasses a number of skeletal dysplasias that show stippled calcification in radiographs of the epiphyses, periarticular tissues, and growth-plate zones throughout the skeleton. At least three defined genetic skeletal dysplasias are associated with this appearance. 116,117 These disorders have been referred to by a variety of names, including Conradi's disease, chondrodystrophica calcificans congenita, punctate epiphyseal dysplasia, and stippled epiphyses. Furthermore, stippling of the epiphyses

826

SILLENCE ET AL


may be found in a variety of diseases, including the cerebrohepatorenal syndrdme (Zellweger), multiple epiphyseal dysplasia, GM1 gangliosidosis, several mucolipidoses, and mucopolysaccharidoses,121 the Smith-LemliOpitz syndrome,122 trisomy 18, trisomy 21, anencephaly, cretinism, and peripheral resistance to thyroxine.85'116 Variable degrees of punctate epiphyseal calcification may also be observed in epiphyses in the fetal Warfarin syndrome,18-'19 fetal hydantoin syndrome,120 and some congenital infection syndromes such as those produced by cytomegalovirus and rubella. 116,120 The three genetic skeletal dysplasias that can be distinguished are a severe autosomal recessive rhizomelic form, an autosomal dominant form (Conradi-Hfilnermann), and a milder, recently delineated, x-linked form.117 In general, all three forms have a characteristic hypoplasia of nasal cartilage and shortening of the columellae, prodpcing flattening of the nasal tip, and may be associated with erythroderma. Congenital cataracts often occur with the autosomal syndromes. The detailed radiographic findings are beyond the scope of this review but can be found in a number of recent publications. 24,25,38116 Rhizomelic Chondrodysplasia Punctata. Rhizomelic chondrodysplasia punctata is characterized by severe rhizomelic shortening of the extremities.25 116 Neonatal respiratory distress is not uncommon, and most of these patients die in infancy. Chondro-osseous tissue abnormalities have been studied in a number of patients.25',116,123,125-128 Although a variety of abnormal features have been observed, they have been inconsistent. The degree of disorganization in the growth plate may be age-related. Most authors, however, agree that there is increased vascularization of reserve cartilage.35 This zone also exhibits dysplastic areas with fibrosis, loose myxoid connective tissues, dysplastic calcification, and microcystic degeneration (Figure 4B). In some growth plates, proliferative chondrocytes are depleted and endochondral ossification is abnormal, with decreased vascular invasion and tongues of cartilage extending into the metaphyses. In other areas endochondral ossification appears normal. Conradi-Hflnermann Chondrodysplasia Punctata. This is generally less severe than the rhizomelic type, and the short stature in this disorder is not rhizomelic in distribution but is frequently asymmetrical.24"'6 Considerable intrafamilial variability of expression has been observed in this autosomal dominant trait.24"'6"20"29 Chondro-osseous tissue abnormalities have been described in a number of patients.24"'630 133 Proliferative cartilage showed areas of myxoid degeneration and cyst formation with excessive fibrous tissue and dysplastic


SKELETAL DYSPLASIAS

827

calcification similar to that observed in rhizomelic chondrodysplasia. Endochondral bone formation has been abnormal in some growth plates and normal in others in the same patient (Figure 4C). In one patient studied, fibrous scarring of the growth plate with fibrous ossification was observed. Different degrees of scarring in different growth plates could account for the asymmetry in this disease. Sex-Linked Chondrodysplasia Punctata. Based on two cases, this variety appears to be milder than the rhizomelic type and shows the flattened facial profile and short stature seen in the Conradi-Hflnermann type but without cataracts or asymmetry of the skeleton. These patients also had mental retardation, and one had mild ichthyosis. The existence of a sex-linked variety of chondrodysplasia is presumed because of its occurrence in male first cousins. Further evidence to support this hypothesis comes from the finding of an excess of males with a mild variety of chondrodysplasia in a study of 23 cases that could not be classified as either the rhizomelic or Conradi-Htlnermann variety.'20 No histopathologic findings have been reported in this variety of chondrodysplasia to date. Campomelic Dysplasias

This is a group of disorders characterized by short-limbed dwarfism with bowing or bending of the long bones, particularly in the lower limbs, pretibial skin dimples, peculiar facies, cleft palate, hypotonia, absence of olfactory nerves, and respiratory distress, which usually results in neonatal death.134-146 Campomelia (bent limbs) may also occur in newborns with various forms of osteogenesis imperfecta (at least four varieties) 37 and hypophosphatasia (dominant and recessive varieties).'37 A case with unusual bowing of the limbs has been reported,'40 where there was overlap of features with congenital osteogenesis imperfecta and congenital hypophosphatasia. The long bones may also be curved in thanatophoric dysplasia. Three syndromes have been distinguished:'38",39 1) long-limbed campomelic dysplasia, in which the bent bones are of normal width and only slightly shortened; 2) short-limbed campomelic dysplasia, normocephalic type; and 3) short-limbed campomelic dysplasia, craniosynostotic type. This latter variety is associated with cloverleaf skull deformity and hydrocephalus. Long-Limbed Campomelic Dysplasia. All these cases have shown shortening and anterior bowing of the femurs and tibias with a subcutaneous dimple overlying the tibial bend. Severe respiratory distress, leading to early death, has been present and presumably results from a combina-

828

SILLENCE ET AL


tion of the small thoracic cage, narrow larynx, and hypoplasia of the cartilagenous tracheal rings. 134,141 Many congenital abnormalities are associated with this skeletal dysplasia,138'139 which is most likely inherited in an autosomal recessive fashion.138 Chondro-osseous tissue abnormalities have been reported in a number of cases. 134"38"139,141-145 Generally, the disorganization observed in the growth plate has been relatively mild with a normal progression of resting and proliferative chondrocytes and normal endochondral ossification (Figure 4C). However, the resting chondrocytes have appeared vacuolated. In one report the chondrocyte columns were shortened and irregular.144 The osseous trabeculas converge towards the maximal point of angulation in the long bones and run at right angles to the longitudinal axis of the shaft at this point 138,139 (Figure 4D). Short-Limbed Campomelic Dysplasia, Normocephalic Type. These patients have shortening of both upper and lower limbs with moderate bowing of the humeri as well as bowing of the lower limbs. They can be distinguished radiographically from patients with the long-limbed campomelic syndrome.138"39 Affected siblings with normal parents have been reported. Further evidence is required to determine the pattern of inheritance of this type. Short-Limbed Campomelic Dysplasia With Craniosynostosis. The distinction between the normocephalic and craniosynostotic types is based on two reported cases.138'139 One patient showed the typical cloverleaf skull deformity (craniosynostosis with hydrocephalus). The other patient had a less severe skull deformity, flattening of the occipital region, and fused coronal and lambdoid sutures. Radiographically, the long bones in both the upper and lower limbs were short and wide with smooth metaphyses. The vertebral bodies showed radiating radiolucent centers, and both infants had bilateral radiohumeral synostosis. Other congenital abnormalities were present. The inheritance is unknown. Chondro-osseous histopathology has not been studied. Achondroplasia

Achondroplasia is a clearly delineated form of short-limbed short stature and is the most common of the chondrodystrophies. The name achondroplasia has been widely and erroneously used to describe a great variety of neonatal short-limbed dysplasias. At birth, infants with achondroplasia classically have short-limbed rhizomelic short stature, a relatively normal trunk, and a large head with a bulging forhead, a depressed nasal bridge, and a relatively prominent mandible. 33'3-39,148,149 Perinatal death is rare. The radiographic changes in the pelvis, lumbar spine, and long bones at


SKELETAL DYSPLASIAS

829

birth are diagnostic.35-39"148 There are short, broad limb bones, especially proximally, lumbosacral narrowing in the spine, and a pelvis with flattened acetabulums and small sacrosciatic notches. Achondroplasia is an autosomal dominant trait with wide clinical variability. Over 80% of the patients have no known family history and can be considered to represent new mutations.150'151 Among sporadic cases, increased paternal age has been found.15' Chondro-osseous histopathology has been studied by a number of authors. Contrary to earlier statements in text books of histopathology, the growth plate is structurally regular with well organized endochondral ossification 71,74,75,152 (Figure 5A). Column formation appears normal. The number of cells per column does not differ significantly from that of agematched controls, but the primary trabeculas may be slightly wider. Periosteal ossification is relatively increased, with periosteal bone extending past the growth plate onto the perichondrium of the resting cartilage, producing the cupping seen radiographically at the rib ends and at some other growth plates. Ponseti 153 and Stanescu and colleagues 77,154 have described histologic abnormalities in achondroplastic fibular and tibial growth plates, respectively. Although they observed a normal progression in the chondrocyte development, some areas of the growth plate showed ovoid clumps of proliferative chondrocytes separated by broad fibrous septa. In these areas the primary calcified trabeculas were broad, short, and arose less regularly than normal. Taken together, all three studies demonstrate that endochondral ossification is only slightly disorganized in achondroplasia. Ultrastructurally the cartilage in achondroplasia contains relatively normal chondrocytes and matrix.74'75 The abnormalities observed are a relative increase in the number of dead cells surrounded by scars consisting of focal aggregations of collagen fibrils 74 and an increased number of membrane-bound intracellular inclusions containing electrondense granules and thread-like material.77 Homozygous Achondroplasia. This condition occurs rarely and is suspected when two achondroplastic parents have a child whose abnormalities are more severe than those of typical achondroplasia. It is clinically, radiologically, and histologically quite distinct from thanatophoric dysplasia and other neonatal skeletal dysplasias, as well as from heterozygous achondroplasia.4 35 These infants usually die during the first three months of life due to respiratory embarrassment,4 35 but some affected infants have been known to survive to several years of age.266 The radiologic features are more severe than those usually seen in achondroplasia and include moderate platyspondyly.4,35 We have studied several cases histopathologically. Chondro-osseous

830

SILLENCE ET AL


tissue showed both normal and abnormal areas of endochondral ossification. In the latter there was absence of regular column formation, with a short growth zone and a wide zone of randomly disposed hypertrophic chondrocytes (Figure 5B). Periosteal bone formation was normal, and there was periosteal overgrowth resulting in cupping of the epiphyseal cartilageA5,71 Diastrophic Dysplasia

Diastrophic dysplasia is a generalized disorder of connective tissue in which dysplastic changes occur in oral, tracheal, articular, as well as chondro-osseous tissues.8" In addition to shortening of both the trunk and extremities, affected individuals often have club hands and feet, hitchhiker thumb deformity, cauliflower ear deformities, symphalangism, cleft palate, and an unusual combination of increased joint laxity in some joints and contractures in others.86"56-1" The radiographic changes include hypoplasia of epiphyses and flaring of metaphyses in most long tubular bones, carpal bone irregularities, including the presence of extra carpal bones, and twisted or fused metatarsals with equinovarus deformity of the ankle.36'89,156"163 It is inherited as an autosomal recessive trait with considerable variability in its expression. 157,164 The histologic and histochemical abnormalities in diastrophic dysplasia are unique. In the resting cartilage chondrocytes are irregularly distributed within lacunas, often containing 3-4 cells, compared to the 1-2 chondrocytes per lacuna normally observed. Individual chondrocytes are enlarged and ovoid in shape. Many appear to be degenerating and are encircled by a peculiar rim of debris. Silver methenamine staining reveals that there is a greater than normal accumulation of collagen fibrils around these cells. Fibrous lesions of varying size are found in the resting cartilage in areas devoid of cells (Figure 5C). The smaller lesions consist of thickened collagen fibrils lying in amorphous material whose staining indicates it is chondroitin sulfate. Both the collagen fibrils and proteoglycan are lost in the larger lesions, leaving cystic spaces. Fibrovascular tissue may be seen in these spaces, and in some instances intracartilaginous ossification is found. The fibrous lesions appear to originate in the resting cartilage but may occasionally extend into and disturb the growth plate, which is shorter than normal and composed of slightly larger but otherwise normal cells.8" Scheck and colleagues have recently shown that resting chondrocytes contain larger than normal amounts of glycogen.'6 They observed that mucopolysaccharide was generally reduced in the diastrophic cartilage.'" Ultrastructurally the degenerating chondrocytes are encircled by clumps of proteoglycan and other cellular debris, which are in turn surrounded by bands of circum-


SKELETAL DYSPLASIAS

831

ferentially oriented collagen fibrils (Figure 5D). The intact cells appear normal, although they contain large amounts of glycogen. A thickening of collagen fibrils is found throughout the matrix, which in general is more fibrillar than normal. 35'75"6566 Metatropic Dysplasia

Metatropic dysplasia is probably a heterogeneous group of disorders, with both autosomal recessive and dominant varieties, characterized by short extremities, bulbous enlargement of the joints, joint limitation, and progressive and severe kyphoscoliosis.36'38"67`68 Radiographically there is marked shortening of tubular bones, which have a barbell-like enlargement of their metaphyses and dysplastic epiphyses. Severe platyspondyly is found, and the iliac crest is flared, giving a "battle-ax" (Halberd) appearance to the pelvis.35-39"167 Histologically, the resting cartilage matrix appears normal; however, resting chondrocytes are more vacuolated than normal and contain metachromatic inclusions." At the growth plate, cell proliferation and maturation appear to be normal; however, vascular invasion is very irregular and foci of unossified cartilage extend into the metaphysis 77 (Figure 6A). These are distinguished from saw (biopsy) dust as they are observed in serial sections throughout the cartilage biopsy. Jenkins has described a thick band of calcified cartilage bridging the chondro-osseous junction.169 Electron microscopy further demonstrates the cytoplasmic vacuolation 77 (Figure 6B). These vacuoles may be both membrane-bound and non-membrane-bound and contain beaded stringlike material lying in clumps of glycogen (Figure 6B). Chondroectodermal Dysplasia (Ellis-van Creveld Syndrome)

This type of dysplasia is characterized by short-limbed dwarfism, postaxial polydactyly, congenital heart disease (usually atrial septal defect), and a variety of ectodermal abnormalities, including dysplastic fingernails and teeth, epispadias, and oral anomalies.35"170-175 Natal teeth are often present. The radiographic changes are diagnostic although very similar to those seen in asphyxiating thoracic dysplasia (Jeune syndrome).38" 74'175 It is inherited as an autosomal recessive trait. A variety of histologic changes have been observed. In the proximal femoral epiphysis, Smith and Hand reported irregular spaced lacunas, abnormal chondrocyte nuclei, and islands of cartilage in metaphyseal bone.'76 Uehlinger has described the protrusion of bone into the epiphyseal cartilage.'77 From examining chondro-osseous tissue from supernumery digits, Stanescu and colleagues have recently reported irregular column formation and vascular invasion, concavity of the epiphyseal line protruding into the cartilage, and islands of cartilage along the periosteum

832

SILLENCE ET AL


and within the metaphyseal bone." In rib and iliac crest biopsies from one of our patients the resting cartilage contained abnormally large chondrocytes, often with several cells per lacuna (normally 1-2), increased vascularity of the cartilage, and a particularly fibrous-appearing matrix, in which areas of degeneration were found (Fig 6C). The growth plate and bony trabeculas, however, appeared normal.35The inconsistency in the findings may represent differences in the endochondral abnormalities in different growth plates. Asphyxiating Thoracic Dysplasia

Asphyxiating thoracic dysplasia (Jeune syndrome, ATD) is a rare autosomal recessive form of short-limbed dwarfism associated with an extremely small thorax and severely limited thoracic expansion. Death often results from respiratory insufficiency during infancy; however, if the child survives this period, respiratory symptoms decrease with age.35178'183 Many, though, develop progressive renal diseases with age. This appears to be due to a mixture of glomerular and interstitial disease.'80-183 Radiographically, the thorax is very small, with short horizontally oriented ribs. ATD must be differentiated from chondroectodermal dysplasia (Ellis-van Creveld syndrome) and the short-rib polydactyly dysplasias.174"179"184 The histologic abnormalities that have been reported are variable and include reduction in the number of proliferating and hypertrophic chondrocytes,78 irregular vascular invasion,356f9 and the presence of cartilage islands within the metaphysis.35'6ff78 Yang and colleagues have also described a transverse bony plate that extends across the metaphysis in severely affected bones. In two other children with this syndrome they have reported poorly mineralized cartilage matrix spicules extending into the metaphyses but not cellular cartilage islands, as in previous cases.78 We have examined iliac crest cartilage from two patients and observed short, slightly irregular columns separated by broad septums (Figure 6D). The bony trabeculas within the metaphysis were wider than normal, particularly adjacent to the zone of vascular invasion, where they often adjoined to form a plate beneath the chondro-osseous junction. There were areas of loose fibrous tissue containing few cells within the resting cartilage. Many of the fibers in these lesions stained for collagen, whereas the background stained for proteoglycan. No cartilage islands were seen within the bone. At the electron-microscopic level, excessive numbers of lipid inclusions in the chondrocytes have been reported. In many cells multilocular lipid inclusions actually distorted cells.186 Many workers believe there may be genetic heterogeneity that accounts for the various presentations of asphyxiating thoracic dysplasia.


SKELETAL DYSPLASIAS

833

Spondyloepiphyseal Dysplasias

Spondyloepiphyseal dysplasias are a heterogeneous group of disorders associated with dysplastic epiphyses, platyspondyly, and vertebral irregularity with varying degrees of metaphyseal abnormalities. They are commonly separated into spondyloepiphyseal dysplasia congenita and spondyloepiphyseal dysplasia tarda. However, a large number of patients with spondyloepiphyseal dysplasia do not have either of these disorders, and further subelassification of the spondyloepiphyseal dysplasias will be necessary in the future. 188-190 Spondyloepiphyseal dysplasia congenita (Spranger-Wiedemann syndrome) is a generalized disorder of connective tissue.22'23 In addition to marked short-trunk stature, affected individuals have a variety of nonskeletal abnormalities such as myopia, often leading to retinal detachment, cleft palate, club foot, and cervical spine instability due to odontoid hypoplasia. Roentgenographically, there is universal platyspondyly, shortening of all long bones, and severe dysplasia of all epiphyses. The proximal femoral epiphyses are most severely affected, resulting in marked coxa vara. Some degree of odontoid hypoplasia is usually seen.22,23,35-39 The histopathologic changes consist of regular chondrocyte proliferation and maturation in most cases, although the columns are somewhat short and the septums wide. In some areas, however, the matrix is quite hypocellular and associated with irregular vascular invasion from the metaphysis.35'74 Chondrocytes in all zones contain cytoplasmic inclusions, which by electron microscopy are dilated endoplasmic reticulum75187 (Figure 7A). Williams and colleagues also noted a microcystic zone near the origin of the proliferative zone, which consisted of "rings of cells" encircling areas of abnormally reticulated matrix.187 In addition, the resting chondrocytes adjacent to this area displayed marked proliferation of Golgi apparatus and were more vacuolated than usual.187 The variability and heterogeneity among the spondyloepiphyseal dysplasias has been the subject of a number of recent views.188-190 Many patients remain to be classified.'90 Morphologic observations will without doubt be important in the future classifications of these conditions. The patients we have observed with unclassifiable spondyloepiphyseal dysplasias have shown a variety of histopathologic abnormalities.190 Kniest Dysplasia

Kniest dysplasia is a generalized disorder of connective tissue characterized by short-trunk dwarfism, kyphoscoliosis, flat round facies, cleft palate, myopia, and joint limitation. It is inherited as an autosomal dominant

834

SILLENCE ET AL


trait.36 The radiographic changes in the long bones resemble those of metatropic dwarfism. However, there is no other resemblance between these two conditions. Diagnostic features include coronal clefts, particularly in lumbar vertebrae; hypoplastic iliac bones with wide irregular acetabular margins; dysplastic femoral heads, which are very delayed in appearance; and short, thin tubular bones with flared metaphyses. Epiphyseal ossification is irregular and punctate; with age, a peculiar stippling occurs at the epiphysis and adjacent metaphysis. 36ff 91194 Rib and iliac crest biopsies from several patients studied to date have revealed a consistent pattern of chondro-osseous disease. Large areas of abnormal matrix composed of multiple vacuoles of varying size lying within a delicate septal network are found (throughout the growth plate and resting cartilage, especially that adjacent to the growth plate). Within these lesions degenerating chondrocytes with vacuolated lacunas have been seen. The septums do not stain with collagen stains, and in some areas they are lost, so that large Swiss-cheese-like vacuoles remain (Figure 7B). Despite these abnormalities, cells within the growth plate attempt to form columns, but maturation is poorly organized and vascular invasion irregular. Moreover, the septums between the columns are wider than normal and often filled with the vacuolar material.74 94'" In the reserve cartilage zone the vacuolar lesions are less common, and the resting chondrocytes are larger than normal and contain cytoplasmic inclusions.'96 Electron micrographs show these to be dilated cisternae of endoplasmic reticulum 76 (Figure 7C). In one patient studied, fibrous long-spacing collagen was observed in the matrix around the degenerating or dead chondrocytes by electron microscopy (Figure 7D). However, this finding is nonspecific and has been found in several disorders.'97 Mesomelic Dysplasias

These are a heterogeneous group of skeletal dysplasias characterized by shortening predominantly in the radioulnar and tibiofibular segments of the limbs. They have different modes of inheritance. Five syndromes, which are manifest at birth, are clearly delineated and named types Nievergelt, Langer, Robinow, Rheinhardt-Pfeiffer, and Werner.'2'38.'98 A number of other dysplasias have been defined with mesomelia, short stature, and other congenital abnormalities that do not fit into these broad categories.'98-204 Probably the commonest mesomelic dysplasia, dychondrosteosis (discussed later), is not manifest until late childhood." The histologic characteristics of these conditions are essentially unknown. Acromesomelic Dysplasias

At least two dysplasias affecting predominantly the forearms, hands, and feet can be recognized at birth.'7'206'207 Growth in these disorders is


SKELETAL DYSPLASIAS

835

markedly disturbed. The face is normal and the trunk only slightly disturbed. These disorders can be distinguished radiologically. No specific histologic characteristics have been reported. Skeletal Dysplasias Identifiable in Later Life Hypochondroplasia

Hypochondroplasia is a distinct disorder which resembles, but is milder than, achondroplasia.73'208 It is usually not evident at birth. Affected individuals tend to have a stocky or muscular build, and the shortening of their limbs, which mainly involves proximal segments, is often quite subtle. The hands are short, but do not have the trident appearance of the fingers that is seen in achondroplasia, and the head and facial structures are usually normal. 736'208'209 Hypochondroplasia is an autosomal dominant trait, and the mutant gene may be allelic with achondroplasia.'55 The radiographic changes suggest mild achondroplasia with a slight degree of shortening of the vertebral pedicles and tubular bones, together with a relative lengthening of the fibula compared to the tibia. The skull and pelvis vary in appearance, from mildly achondroplastic to completely normal. 7,35,38,208

Histologic studies have demonstrated an essentially normal-appearing endochondral growth plate although the matrix septums may be slightly wider than normal. Periosteal overgrowth is not found, as it is in achondroplasia.35 Ultrastructural studies show normal growth-plate matrix and chondrocytes.72 75 Dyschondrosteosis

This dysplasia produces mild short stature and mesomelic shortening of the extremities with a Madelung-like deformity of the distal forearm.11'210-212 The radius and ulna are disproportionally shortened and appear wide. It is probably inherited as an autosomal dominant trait with increased severity in females.35 Specific histopathologic findings have not been reported. Metaphyseal Dysplasia

The metaphyseal dysplasias, formerly the metaphyseal dysostoses, are a heterogeneous group of disorders characterized by involvement predominantly of the metaphyses with relatively normal epiphyses and a normal spine.3'213'2" The most severe and least common is the Jansen type, which produces severe shortening, particularly of the legs. In this variety, radiographs show enlargement and cystic changes in all metaphyses.215-219 This type of dysplasia is thought to be inherited as an autosomal

836

SILLENCE ET AL


dominant trait.36'218 A more common form, the Schmid variety, is also inherited in autosomal dominant fashion and is characterized by mild to moderate short stature, bowing of the legs, and a waddling gait. The radiographically observed changes are less severe and are found in the hips, knees, shoulders, ankles, and wrists. 35'38'220222 In the McKusick type (cartilage-hair hypoplasia), which is an autosomal recessive trait, there is severe growth deficiency of postnatal onset with particularly short, broad hands and very loose joints of the hand and wrist. In addition, these individuals have an ectodermal dysplasia that is manifested by fine, light sparse hair and a light complexion."' 223-226 An increased susceptibility to severe varicella infection has been reported as part of a deficiency in cellular immunity, shown by chronic neutropenia, lymphopenia, diminished skin hypersensitivity, and delayed rejection of skin allografts.227'228 The changes seen radiographically are most severe at the knee, where there is distal overgrowth of the fibula, compared with the tibia.35'38'223 The combination of metaphyseal abnormalities and immune deficiency is found in at least three other syndromes: 1) the Schwachman syndrome, in which the skeletal lesions are associated with pancreatic exocrine insufficiency and neutropenia 229,230; 2) the metaphyseal chondrodysplasiathymolymphopenia syndrome 233-236; and 3) severe combined immunodeficiency disease due to adenosine deaminase deficiency, in which mild short stature and flaring of the ribs may occur.237 23' All three syndromes are inherited as autosomal recessive traits. From examining biopsy specimens from patients with several different forms of metaphyseal chondrodysplasia, we and others have found that the histopathologic changes are quite similar in the Jansen, Schmid, and McKusick types and metaphyseal dysplasia with thymolymphopenia. The chondrocytes are larger than normal and lie in an unusually fibrillar matrix. Clusters or nests of proliferating and hypertrophic cells are found at the growth plate, instead of linear columns (Figure 8A). They appear to be surrounded by dense fibrous material, and the matrix separating these nests is much wider than normal. Metaphyseal vascular invasion is irregular and in some areas does not occur, permitting the nests of hypertrophic cartilage to extend in a tongue-like fashion into the metaphysis.357'74'239'240 Cooper and colleagues have reported that by electron microscopy the chondrocytes at all levels of the epiphyseal growth plate contain dilated cisternae of endoplasmic reticulum.239'240 We have studied several cases and have not observed these inclusions. The question has been raised as to whether the case studied by Cooper and colleagues was a form of spondylometaphyseal dysplasia, in which such inclusions have also been noted." The histologic characteristics of the cartilage that are observed in the


SKELETAL DYSPLASIAS

837

Schwachman syndrome are similar to the other forms of metaphyseal chondrodysplasia. In adenosine deaminase deficiency, there is an almost complete lack of chondrocyte proliferation and maturation at the growth plate 238 (Figure 7B). Many degenerating cells are seen, often within large irregular lacunas. The chondro-osseous junction consists of a rather abrupt transformation of cartilage into metaphyseal bone, and there is a tendency for the bone to form a transverse bridge across the metaphyseal portion of the growth plate. Osteoblasts and osteoclasts are reduced in number as well.237'238 ,242 By electron microscopy, Spycher has observed dilated cisternae of endoplasmic reticulum in growth plate chondrocytes in one case of the Schwachman syndrome.242 Spondylometaphyseal Dysplaslas

These are conditions in which the radiologic abnormalities are primarily localized to the vertebrae and metaphyses. In the one well-defined variety, described by Kozlowski,243 growth retardation is usually not apparent until 1-2 years of age. The face is normal. There is short-trunk short stature with shortening, waddling gait, and, in some patients, mild pectus carinatum, kyphoscoliosis, and precocious osteoarthritis. This condition is inherited in an autosomal dominant fashion.8214243 Chondro-osseous tissues have been reported to show a reduced proliferative zone and irregular formation of cartilage columns.8 We have studied rib and iliac crest tissue from three patients, and they have shown nonspecific changes. The growth plate has been irregular, with cartilage columns of varying length and the fibrillar appearance of the intercolumnar matrix, with irregular vascular penetration of the cartilage, similar to that reported by other authors." Ultrastructural studies have been reported showing patterned or granular inclusions in chondrocytes from the reserve cartilage but rarely in chondrocytes from the proliferative zone.77 Multiple Epiphyseal Dysplasias

At least two autosomal dominant dysplasias and one autosomal recessive condition have been described with short stature and radiologic evidence of small, flattened, or fragmented epiphyses throughout the skeleton. These have been called multiple epiphyseal dysplasias or polyepiphyseal dysplasias.35 38 In the dominantly inherited Fairbank variety 244,245 the epiphyses are small during childhood, and there are marked epiphyseal and metaphyseal changes in the metacarpals and phalanges.3'38 In the milder dominant Ribbing type 246 the epiphyses are flattened, with mild to normal radiographically also visible changes in the hands.35'38 There is wide variability between families and some overlap

838

SILLENCE ET AL


between these types radiographically, which may point to further genetic heterogeneity.38 In the pedigrees showing recessive inheritance, there has been a much higher frequency of scoliosis and congenital talipes. Chondro-osseous tissue has been reported to be essentially histologically normal at the iliac crest and costochondral junction,35'77'245 although a variety of histochemical abnormalities in cartilage matrix 256 and vacuolization of the chondrocytes with dilatation of rough endoplasmic reticulum (seen by electron microscopy) have been reported 77 (Figure 8C). These latter findings are similar to those observed in various types of spondyloepiphyseal dysplasia. Stanescu and colleagues in 1977 reported histopathologic findings in two cases in which parental consanguinity suggested autosomal recessive inheritance. They observed that most chondrocytes contained clear vacuoles, when seen by light microscopy, that were membrane-bound and contained fine granules and thread-like filaments when seen by electron microscopy.77 These authors suggest that the dominant and recessive varieties of multiple epiphyseal dysplasia can be clearly distinguished by the histochemical and ultrastructural appearance of the inclusion bodies seen in each variety.77 We have studied two siblings whom, we believe, have this syndrome. By light microscopy, we observed in one sibling abnormal condensation of the matrix around cells in the proliferative zone (Figure 8D) similar to the pericellular matrix abnormalities we have observed in some areas of the cartilage in diastrophic dysplasia. Arthro-ophthalmopathy (Stickler)

This dominantly inherited syndrome is characterized by severe myopia with retinal detachment, variable skeletal changes resembling a mild spondyloepiphyseal dysplasia, and premature degenerative arthritis involving especially the knees and hips.35'257-260 Some patients present at birth with the Pierre Robin anomaly, with hyperextensibility of the joints and high myopic astigmatism.261'262 Sensorineural hearing loss may be present in some patients.35 The radiographic findings are those of mild platyspondyly and irregular epiphyses, particularly in the weight-bearing joints. Histopathologic findings have not been reported.35 Pseudoachondroplasia

The pseudoachondroplasias are a heterogeneous group of disorders producing short-limbed short stature with normal craniofacial proportions, which vary in severity and are confused with achondroplasia but are quite distinct from that condition.14 Autosomal dominant and recessive forms have been described.263265


SKELETAL DYSPLASIAS

839

Although four types have been described,263 it is clear that these are not as distinct as previously believed, and in one instance the subsequent reproduction pattern of a family on whom the autosomal recessive inheritance of one type (Type IV) had been based suggests autosomal dominant inheritance.266 Although not apparent until late infancy, the growth deficiency is severe. There is excessive ligamentous laxity in the wrists, hands, and feet; reduced extension at the elbow; flexion contractures of the hips and knees; and precocious osteoarthritis. The long bones may be bowed, particularly the radius and the ulna. Radiographs reveal generalized hypoplasia and irregularity of epiphyses and splaying of the metaphyses of the long tubular bones. The vertebral bodies are flattened and irregular and show anterior tonguing. 35,38,265 Varying degrees of disruption of the growth plate, including diminished cell proliferation and maturation, have been observed.35'267 The resulting chondrocytes are larger than normal and tend to accumulate into groups of two to six within a single lacuna (Figure 9B). These cells, as well as those in the growth plate, contain cytoplasmic inclusions which stain histochemically as protein 33186 (Figures 9A and 9B). Electron micrographs have confirmed that these inclusions are dilated cisternae of endoplasmic reticulum. With the use of double fixation with aldehydes and osmium, these inclusions have been observed to consist of alternating electron-dense and electron-lucent lamellas 268-271 (Figures 9C and 9D). However, using primary osmium fixation, we have observed a more diffuse pattern of alternating electron-dense and lucent granular areas. Spondyloepiphyseal Dysplasia Tarda

Spondyloepiphyseal dysplasia tarda is an x-linked skeletal dysplasia characterized by short-trunk short stature with epiphyseal dysplasia leading to premature osteoarthrosis. Growth failure does not become apparent until 5-10 years of age.36'272-274 The radiographic findings in the spine are distinct and diagnostic. In the lateral view, vertebrae show a humpshaped buildup of bone in the central and posterior portions of the superior and inferior plates.36'39 The epiphyses remain unossified until late in childhood, and the vertebral spaces are narrowed. We have studied two patients, both immediately prepubertal, from two x-linked pedigrees with this disorder. Chondro-osseous tissue showed essentially normal chondrocyte maturation, although the clustering of proliferative chondrocytes appeared greater than usual, and in one patient closure of the iliac crest growth plate appeared more advanced for his age than usual.

840

SILLENCE ET AL


Spondyloepiphyseal Dysplasia, Other Forms

The variable clinical, radiographic, and growth-plate histopathologic findings in the forms of spondyloepiphyseal dysplasia have been the subject of several recent reviews. 189-190 A variety of morphologic abnormalities have been observed. Of particular interest are the findings in a recently described new variety of spondyloepiphyseal dysplasia with autosomal or x-linked dominant inheritance and punctate corneal dystrophy.275 These patients show a focal accumulation of abnormal collagen fibers in the deep reticular dermis. In these areas short lengths of collagen fibers with normal periodicity appeared to be abruptly dissociated into a tightly twisted network of fibrils at both ends.275 The morphologic characteristics of cartilage collagen in this condition have not been reported. Dyggve-Melchior-Clausen Syndrome

The Dyggve-Melchior-Clausen syndrome is a rare autosomal recessive disorder characterized by short-trunk dwarfism, exaggerated lordosis, long knobby fingers, and in some patients mental retardation. Radiographs reveal severe platyspondyly, together with generalized flattening and irregularity of epiphyses and flaring of metaphyses. In children there is a distinctive lacy appearance to the iliac crest that extends from the acetabular margin to the top of the crest.35,38'276-279 Although earlier reports suggested that affected individuals had mucopolysacchariduria,276'277 subsequent studies have shown that this is not the case.279 Histologic studies from two cases of Dyggve-Melchior-Clausen syndrome showed the presence of numerous focal collections of dying and dead cells scattered throughout the resting cartilage, which was otherwise relatively acellular (Figure 10A). The foci may contain from 2 to 20 cells and are surrounded by a dense ring of fibrous material. Amorphous interacartilaginous ossification is also seen in the resting cartilage.36 The clusters appear ultrastructurally to be separated from the remaining matrix by a fibrous capsule composed of fibers of varying thickness together with calcium deposits and other debris 75 (Figure lOB). Spondyloepimetaphyseal Dysplasias

These are a heterogeneous group of conditions with abnormalities in vertebrae (platyspondyly), epiphyses, and metaphyses. When the involvement is more marked in the metaphyses than epiphyses, they are known as spondylometepiphyseal dysplasias. These conditions are rare, and the groups are poorly defined radiologically. We have defined one specific form of spondylometepiphyseal dysplasia


SKELETAL DYSPLASIAS

841

with dappled metaphyses and epiphyses 280,281 in which the histopathologic changes in one case studied in rib and iliac crest are, to date, unique, with hypocellularity of the rib cartilage, compared with the iliac crest 190 (Figure lOC). Ultrastructurally, chondrocytes show abnormal moderately dilated rough endoplasmic reticulum containing a homogeneously staining granular material 190 (Figure lOD). Myotonic Chondrodysplasia (Catel-Schwartz-Jampel)

This is a unique variety of spondyloepimetaphyseal dysplasia associated with mild myotonic dystrophy in affected individuals. These patients have characteristic pinched facies with congenital blepharophimosis and puckered lips. Radiographically there is generalized platyspondyly, small irregularly shaped epiphyses, irregular metaphyses, and severe coxa vara; the thorax has a paralytic configuration, narrow superiorly with oblique ribs. 282-287

Chondro-osseous histopatholic characteristics have not been reported. Parastrem matic Dysplasia

This is a rare skeletal dysplasia characterized by severe short stature, kyphoscoliosis, distortion and bowing of the extremities, particularly the lower limbs, and contractures of the large joints. 13,35,38,287,288 Radiographic features include generalized osteoporosis, widened metaphyses, and an osteo-dense stippling extending across both epiphyses and metaphyses with age. The inheritance pattern is unknown, although father to daughter transmission in one instance suggests autosomal or x-linked dominant inheritance. Endochondral bone formation appeared irregular with complete lack of columnization of cartilage cells and reduced numbers of osteoblasts and osteoclasts.13'288 Trichorhinophalangeal Dysplasias

The main features are deficient growth, a pear-shaped nose, deformities of the fingers with brachymetacarpophalangism and swelling of the interphalangeal region. There are Perthes'-like changes in the hips in childhood and progressive arthritic symptoms of the thoracic spine, elbows, and fingers.35'38'290 Chondro-osseous morphologic characteristics have not been reported. Conclusion In view of the diagnostic value of chondro-osseous morphology in the differentiation of the skeletal dysplasias, we urge all pathologists to routinely save samples of growth plate, eg, the iliac crest, the costochondral

842

SILLENCE ET AL


junction, long bone where possible, and a segment of vertebral growth plate, from autopsies on all individuals who have died because of skeletal dysplasias. Although considerable progress has been made in our knowledge of the histopathologic characteristics of these conditions-and specific findings have been discovered in a large number of disorders-there remain gaps in our knowledge of the histopathologic characteristics, histochemical characteristics, and ultrastructure. These gaps result in part from the variability in the site of biopsy; the variability in fixation and embedding methods; the availability of biopsy tissue versus autopsy tissue; and the lack of precise clinical, radiographic, and genetic definition in the past of the conditions studied. Furthermore, the rarity of many of these disorders has made the collection of a number of samples sufficient to document their characteristic morphologic abnormalities a slow and difficult process. In view of these problems, we have been funded by the National Institutes of Health and the National Foundation March of Dimes to create an international registry for the collection, processing, and analysis of chondro-osseous tissue in this group of disorders. References 1. International nomenclature of constitutional diseases of bone. J Pediatr 93:614-616, 1978 2. Rubin P: Dynamic classification of bone dysplasias. Chicago, Year Book Medical Publishers, 1964 3. Giedion A: Das tricho-rhino-phalangeale Syndrome. Helv Paediatr Acta 21:475482, 1966 4. Giedion A, Prader A, Hadorn B, Shmerling DH, Auricchio S: Metaphysare dysostose und angeborene pankreasinsuffizienz. Fortschr Roentgenstr 108:51-57, 1968 5. Hall JG, Dorst JP, Taybi H, Scott CI, Langer LO Jr, McKusick VA: Two probable cases of homozygosity for the achondroplasia gene. Birth Defects 5(4):24-34, 1969 6. Kozlowski K: Metaphyseal dysostosis: Report of five familial and two sporadic cases of a mild type. Am J Roentgenol 91:602-608, 1964 7. Kozlowski K: Hypochondroplasia. Pol Rev Radiol Nucl Med 29:450-459, 1965 8. Kozlowski K: Spondylo-metaphyseal dysplasia. Progress in Pediatric Radiology. Vol 4, Intrinsic Diseases of Bones. Edited by HJ Kaufman. Basel, Karger, 1973, pp 299-308 9. Lamy M, Maroteaux P: Le nanisme diastrophique. Presse Med 68:1977-1980, 1960

10. Langer LO Jr: .Spondyloepiphysial dysplasia tarda: Hereditary chondrodysplasia with characteristic vertebral configuration in the adult. Radiology 82:833-839, 1964 11. Langer LO Jr: Dyschondrosteosis: A hereditable bone dysplasia with characteristic roentgenographic features. Am J Roentgenol 95:178-188, 1965 12. Langer LO Jr: Mesomelic dwarfism of the hypoplastic ulna, fibula, mandible type. Radiology 89:654-660, 1967 13. Langer LO, Peterson D, Spranger J: An unusual bone dysplasia: Parastremmatic dwarfism. Am J Roentgenol 110:550-560, 1970 14. Maroteaux P, Lamy M: Les formes pseudo-achondroplasiques de dysplasies spondylo-epiphysaires. Presse Med 67:383-386, 1959


15. 16. 17. 18.

19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

29.

30. 31. 32.

33. 34.

35. 36. 37. 38.

39.

SKELETAL DYSPLASIAS

843

Maroteaux P, Lamy M, Robert JM: Le nanisme thanatophore. Presse Med 75:2519-2524, 1967 Maroteaux P, Lamy M, Bernard J: La dysplasie spondylo-epiphysaire tardive: Description clinique et radiologique. Presse Med 65:1205-1208, 1957 Maroteaux P, Martinelli B, Campailla E: Le nanisme acromesomelique. Presse Med 79:1839-1842, 1971 Maroteaux P, Spranger J, Wiedemann HR: Der metatropische Zwergwuchs. Arch Kinderheilkd 173:211-226, 1966 McKusick VA: Metaphyseal dysostosis and thin hair: A "new" recessively inherited syndrome? Lancet 1:832-833, 1964 McKusick VA, Egeland JA, Eldridge R, Krusen DE: Dwarfism in the Amish: 1. The Ellis-van Creveld syndrome. Bull Hopkins Hosp 115:306-336, 1964 Scott CI Jr: Achondrogenesis type II (Grebe or Brazilian type). Birth Defects 5(4):14-16, 1969 Spranger JW, Wiedemann HR: Dysplasia spondyloepiphysaria congenita. Helv Paediatr Acta 21:598-611, 1966 Spranger JW, Langer LO Jr: Spondyloepiphyseal dysplasia congenita. Radiology 94:313-322, 1970 Spranger JW, Bidder U, Voelz C: Chondrodysplasia punctata (chondrodystrophia calcificans) Typ Conradi-Hunermann. Fortschr Roentgenstr 113:717-725, 1970 Spranger JW, Bidder U, Voelz C: Chondrodysplasia punctata (chondrodystrophia calcificans): II. Der rhizomele Type. Fortschr Geb Roentgenstr Nuklearmed 114:327-335, 1971 Spranger J, Grimm B, Weller M, Weissenbacher G, Herrmann J, Gilbert E, Krepler R: Short rib-polydactyly (SRP) syndromes, types Majewski and Saldino-Noonan. Z Kinderheilkd 116:73-94, 1974 Spranger JW, Gerken H: Diastrophischer Zwergwuchs. Z Kinderheilkd 98:227234, 1967 Kozlowski K, Maroteaux P, Silverman F, Kaufmann H, Spranger J: Classification des dysplasies osseuses. Table ronde. Ann Radiol 12:965-1007, 1969 Maroteaux P: Nomenclature internationale des maladies osseuses constitutionelles. Ann Radiol 13:455-464, 1970 Scott CI: The genetics of short stature, Progress in Medical Genetics. Vol 8. Edited by AG Steinberg, AG Bearn. New York, Grune and Stratton, 1972, pp 243299 Danks DM: Generalized dysplasias of bone: Some practical considerations, Progress in Pediatric Surgery. Vol 8. Munchen, Urban Z. Schwarzenberg, 1975, pp 135165 Kaufman HJ (ed): Intrinsic Diseases of Bones. Progress in Pediatric Radiology. Vol 4. Basel, Karger, 1973 McKusick VA: Heritable Disorders of Connective Tissue. Fourth edition. St. Louis, C. V. Mosby, 1972 McKusick VA: Mendelian Inheritance in Man. Fifth edition. Baltimore, Md, The Johns Hopkins Press, 1978 Rimoin DL: The chondrodystrophies, Advances in Human Genetics. Vol 5. New York, Plenum, 1975, pp 10-118 Rimoin DL (ed): Skeletal Dysplasias. Clin Orthop 114:2-179, 1976 Sillence DO, Rimoin DL, Lachman R: Neonatal dwarfism. Pediatr Clin North Am 25(3):453-483, 1978 Spranger JW, Langer LO, Wiedemann HR: Bone Dysplasias: An Atlas of Constitutional Disorders of Skeletal Development. Philadelphia, W. B. Saunders, 1974 Maroteaux P: Maladies Osseuses de L'Enfant. Paris, Flammarion MedecineSciences, 1974

844

SILLENCE ET AL


40. Hollister DW, Burgeson RE, Rimoin DL: Abnormal cartilage collagen in thanatophoric dwarfism. Proc Am Soc Human Genet, 26th annual meeting 46A, 1975 41. Kim JH, Beratis NG, Brill P, Raab F, Hirschhorn K, Matalon R: Kniest syndrome with dominant inheritance and muco-polysacchariduria. Am J Human Genet 27:755-764, 1975 42. Stanescu V, Maroteaux P: Anomalies des proteoglycans dans le cartilage de croissance de la pseudo-achondroplasie. C R Acad Sci (Paris) 277:2585-2588, 1973 43. Stanescu V, Maroteaux P: Gel electrophoretic studies on proteoglycans and collagen of abnormal human growth cartilage: Proteoglycan abnormalities in pseudoachondroplasia and Kniest's disease. Pediatr Res 9:779-782, 1975 44. Stanescu V, Stanescu R, Maroteaux P: Inter6t de l'6tude du cartilage de croissance dans les chondrodysplasies. Bordeaux Med 9:1849-1859, 1976 45. Stanbury JB, Wyngaarden JB, Fredrickson DS: The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1978, pp 1340-1349 46. Mulivor RA, Mennuti M, Zackai EH, Harris H: Prenatal diagnosis of hypophosphatasia: Genetic, biochemical and clinical studies. Am J Hum Genet 30:271282, 1978 47. Horton WA, Rimoin DL, Hollister DW, Lachman RS: Further heterogeneity within lethal neonatal short-limbed dwarfism: The platyspondylic types. J Pediatr 94:736-742, 1979 48. Bennett HS, Wyrick AD, Lee SW, NcNeil JH: Science and art in preparing tissues embedded in plastic for light microscopy, with special reference to glycol methacrylate, glass knives, and simple stains. Stain Technol 51:71-97, 1976 49. Horton WA, Rimoin DL: Histochemical characterization of the endochondral growth plate: A new approach to the study of the chondrodystrophies. Birth Defects 14(6B):81-93, 1978 50. Cole MB, Sykes SM: Glycol methacrylate in light microscopy: A routine method for embedding and sectioning animal tissue. Stain Technol 49:387-400, 1974 51. Liew CT: Principles and Practices of Plastic Sections for Light Microscopy. Department of Pathology, University of Southern California School of Medicine, Los Angeles, 1978 52. Glauert AM: Fixation, dehydration and embedding of biological specimens, Practical Methods in Electron Microscopy. New York, American Elsevier, 1974 53. Karnovsky MJ: A formaldehyde-glutaraldehyde fixative of high osmolality for use in electron microscopy. J Cell Biol 27:137A, 1965 54. Spurr AR: A low-viscosity epoxy resin embedding medium for electron microscopy. J Ultrastruct Res 26:31-43, 1969 55. Hamilton R, Sillence DO, Shimono LH, Carpentier C: A method for uniform polymerization of large blocks of chondro-osseous tissue embedded in glycol methacrylate. Stain Technol (In press) 56. Green MR, Pastewka JV: Simultaneous differential staining by cationic carbocyanine dye of nucleic acids, proteins and conjugated proteins: II. Carbohydrate and sulfated carbohydrate containing proteins. J Histochem Cytochem 22:774-781, 1974 57. Scott JE, Dorling J: Differential staining of acid glycosaminoglycans (mucopolysaccharides) by alcian blue in salt solutions. Histochemie 5:221-233, 1965 58. Scott JE, Dorling J, Stockwell RA: Reversal of protein blocking of basophilia in salt solutions: Implications in the localization of polyanions using alcian blue. J Histochem Cytochem 16:383-386, 1968 59. Hirshman A, McCabe DM: The effect of proteolytic enzymes and hyaluronidase on the intracellular ,B and y metachromatic granules and the matrix of rat epiphyseal cartilage. Anat Rec 180:617-628, 1974 60. Culling CFA: Handbook of Histopathological and Histochemical Techniques. Toronto, Butterworths, pp 470-473, 1974


SKELETAL DYSPLASIAS

845

61. Lillie RD, Fullmer HM: Connective tissue fibers and membranes, Histopathologic Technic and Practical Histochemistry. New York, McGraw-Hill, 1976, pp 679-718 62. Luna LG (ed): Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology. New York, McGraw-Hill, 1968, pp 97-99 63. Clark G: Staining Procedures. Baltimore, Williams and Wilkins, 1973, pp 147-148 64. Ackermann GA: Substituted naphthol AS phosphate derivatives for the localization of leukocyte alkaline phosphatase activity. Lab Invest 11:563-567, 1962 65. Rutenberg AM, Kim H, Fishbein JW, Hanker JS, Wasserkrug HL, Seligman AM: Histochemical and ultrastructural demonstration of 7-glutamyl transpeptidase activity. J Histochem Cytochem 17:517-526, 1969 66. Holtrop ME: The ultrastructure of the epiphyseal plate: II. The hypertrophic chondrocyte. Calcif Tiss Res 9:140-151, 1972 67. Anderson HC: Matrix vesicles of cartilage and bone. The Biochemistry and Physiology of Bone. Vol 4. Second edition. Edited by GH Bourne. New York, Academic Press, 1976, pp 135-157 68. Doty S: Personal communication, 1978 69. Houston CS, Awen CF, Kent HP: Fatal neonatal dwarfism. J Can Assoc Radiology 23:45-61, 1972 70. Maroteaux P, Stanescu V, Stanescu R: The lethal chondrodysplasias. Clin Orthop 114:31-45, 1976 71. Rimoin DL, McAlister WH, Saldino RM, Hall JG: Histologic appearances of some types of congenital dwarfism,32 pp 68-92 72. Rimoin DL: Histopathology and ultrastructure of cartilage in the chondrodystrophies. Birth Defects 10(9):1-18, 1974 73. Rimoin DL, Hollister DW, Lachman RS, Kaufman RL, McAlister WH, Rosenthal RE, Hughes GNF: Histologic studies in the chondrodystrophies. Birth Defects 10(12):274-295, 1974 74. Rimoin DL, Silberberg R, Hollister DW: Chondro-osseous pathology in the chondrodystrophies. Clin Orthop 114:137-152, 1976 75. Silberberg R: Ultrastructure of cartilage in chondrodystrophies. Birth Defects 10(12):306-313, 1976 76. Sillence DO, Rimoin DL, Silberberg R: Ultrastructural studies of cartilage in genetic disorders of skeletal growth. Electron Microsc 2:668-669, 1978 77. Stanescu R, Maroteaux P: Morphological and biochemical studies of epiphyseal cartilage in dyschondroplasias. Arch Fr Pediatr 34 (suppl) (3): 1-80, 1977 78. Yang SS, Heidleberger P, Brough AJ, Corbett DP, Bernstein J: Lethal shortlimbed chondrodysplasia in early infancy, Perspectives in Pediatric Pathology. Vol 3. Chicago, Year Book Medical Publishers, 1976, pp 1-40 79. Grebe H: Achondrogenesis ein einfaches rezessives Erbmerkmal. Folia Hered Path 2:23-28, 1952 80. Quelce-Salgado A: A new type of dwarfism with various bone aplasias and hypoplasias of the extremities. Acta Genet (Basel) 14:63-66, 1964 81. Kozlowski K, Masel J, Morris, L, Ryan J, Collins E, Van Vliet P, Woolnough H: Neonatal death dwarfism: Report of 17 cases. Australas Radiol 21:164-183, 1977 82. Parenti GC: La anosteogenesi (una verieta della osteogenesi imperfetta). Pathologica 28:447-462, 1936 83. Fraccaro M: Contributo allo studio delle malattie del mesenchima osteopoitico: I acondrogenesi. Folia Hered Path 1:190-203, 1952 84. Harris R, Patton JT, Barson AJ: Pseudo-achondrogenesis with fractures. Clin Genet 3:435-441, 1972 85. Saldino RM: Radiographic diagnosis of neonatal short-limbed dwarfism. Med Radiogr Photogr 49:61-95, 1973

846

SILLENCE ET AL


86. Urso FP, Urso MJ: Achondrogenesis in two sibs. Birth Defects 10(12):10-17, 1974 87. Wiedemann HR, Remagen W, Heinz HA, Gorlin RJ, Maroteaux P:

88.

89. 90. 91.

92. 93. 94. 95. 96. 97.

98.

Achondrogenesis within the scope of connately manifested generalized skeletal dysplasias. Z Kinderheilkd 116:223-1251, 1974 Yang S-S, Brough AJ, Garewal GS, Bernstein J: Two types of heritable lethal achondrogenesis. J Pediatr 85:796-801, 1974 Yang S-S, Heidelberger KP, Bernstein J: Intracytoplasmic inclusion bodies in the chondrocytes of type I lethal achondrogenesis. Hum Pathol 7:667-673, 1976 Ornoy A, Sekeles E, Smith P, Simkin A, Kohn G: Achondrogenesis type I in three sibling fetuses. Am J Pathol 82:71-84, 1976 Langer LO, Jr, Spranger JW, Greinacher I, Herdman RC: Thanatophoric dwarfism: A condition confused with achondroplasia in the neonate, with brief comments on achondrogenesis and homozygous achondroplasia. Radiology 92:285-294, 1969 Saldino RM: Lethal short-limbed dwarfism: Achondrogenesis and thanatophoric dwarfism. Am J Roentgenol 112:185-197, 1971 Xanthakos UF, Rejent MM: Achondrogenesis: case report and review of the literature. J Pediatr 82:658-663, 1973 Bouvet JP, Maroteaux P, Feingold J: ttude genetique du nanisme thanatophore. Ann Genet (Paris) 17:181-188, 1974 Beaudoing A, Bost M, Pont J, Coulomb M: Nanisme thanatophore: Une observation anatomo-clinique. Pediatrie 24:459-461, 1969 Fruchter Z: Thanatophoric dwarfism,"2 pp 125-136, Goutieres F, Aicardi J, Farkas-Bargeton E: Une malformation cerebrale particuli&e associee au nanisme thanatophore. Rev Neurol (Paris) 125:435-440, 1971 Chemke J, Graff G, Lancet M: Familial thanatophoric dwarfism. Lancet 1:1358, 1971

99. Harris R, Patton JT: Achondroplasia and thanatophoric dwarfism in the newborn. Clin Genet 2:61-72, 1971 100. Graff C, Chemke J, Lancet M: Familial recurring thanatophoric dwarfism. Obstet Gynecol 39:515-520, 1972 101. Sabry A: Thanatophoric dwarfism in triplets (corres). Lancet 2:533, 1974 102. Bloomfield JA: Cloverleaf skull and thanatophoric dwarfism. Australas Radiol 14:429-434, 1970 103. Camera G, Mantegazza F, Damiani S: Associazione tra cranio a trifoglio e nanismo tanatoforo. Pathologica 65:181-187, 1973 104. Camera G, Verri B: Su una nuova osservazione di nanismo tanatoforo associato a cranio a trifoglio. Pathologica 66:105-112, 1974 105. lannaccone G, Gerlini G: The so-called "cloverleaf skull syndrome." Pediatr Radiol 2:175-184, 1974 106. Partington MW, Gonzales-Crussi F, Khakee SG, Wollin DG: Cloverleaf skull and thanatophoric dwarfism: Report of four cases, two in the same sibship. Arch Dis Child 46:656-664, 1971 107. Wiedemann HR, Ostertag B: Kleeblattschadel und allgemeine Mikromelie: Versuch einer nosologischen Zuordnung und genetischen Elternberatung. Klin Paediatr 186:261-263, 1974 108. Young RS, Pochaczevsky R, Leonidas JC, Wexler IB, Ratner H: Thanatophoric dwarfism and cloverleaf skull (" Kleeblattschadel"). Radiology 106:401-405, 1973 109. Saldino RM, Noonan CD: Severe thoracic dystrophy with striking micromelia, abnormal osseous development, including the spine, and multiple visceral anomalies. Am J Roentgenol 114:257-263, 1972 110. Majewski F, Pfeiffer RA, Lenz W, MOller R, Feil G, Seiler R: Polysyndaktylie, verkfirzte Gliedmassen und Genitalfehlbildungen: Kennzeichen eines selbstandigen Syndroms. Z Kinderheilkd 111:118-138, 1971 111. Naumoff P, Young LW, Mazer J, Amortegui AJ: Short rib-polydactyly syndrome type 3. Radiology 122:443-447, 1977

Vol. 96, No. 3

September 1979

SKELETAL DYSPLASIAS

847

112. Verma IC, Bhargava S, Agarwal S: An autosomal recessive form of lethal chondrodystrophy with severe thoracic narrowing, rhizoacromelic type of micromelia, polydactyly and genital anomalies. Birth Defects 11(6):167-174, 1975 113. Bidot-Lopez P, Ablow RC, Ogden JA, Mahoney MJ: A case of short rib polydactyly. Pediatrics 61:427-432, 1978 114. Le Marec B, Passarge E, Dellenbach P, Kerisit J, Signargoot J, Ferrand B, Senecal J: Les formes neonatales lethales de la dysplasie chondro-ectodermique: Apropos de cinq observations. Ann Radiology 16:19-27, 1973 115. Lowry RB, Wignall N: Saldino-Noonan short rib-polydactyly dwarfism syndrome. Pediatrics 56:121-123, 1975 116. Spranger JW, Opitz JM, Bidder U: Heterogeneity of chondrodysplasia punctata. Humangenetik 11: 190-212, 1971 117. Curry CJR, Beam CW, Hall BD: Sex-linked inheritance of chondrodysplasia punctata. Clin Res 26: 193A, 1978 118. Shaul WL, Emery H, Hall JG: Chondrodysplasia punctata and maternal warfarin use during pregnancy. Am J Dis Child 129:360-362, 1975 119. Becker MH, Genieser NB, Finegold M, Miranda D, Spackman T: Chondrodysplasia punctata: Is maternal warfarin therapy a factor? Am J Dis Child 129:356-359, 1975 120. Sheffield LJ, Danks DM, Mayne VM, Hutchinson LA: Chondrodysplasia punctata: 23 cases of a mild and relatively common variety. J Pediatr 89:916-923, 1976 121. Lemaitre L, Remy J, Farriaux JP, Dhondt JL, Walbaum R: Radiological signs of mucolipidosis II or I-cell disease. Pediatr Radiol 7:97-105, 1978 122. Gibson R: A case of the Smith-Lemli-Opitz syndrome of multiple congenital anomalies in association with dysplasia epiphysialis punctata. Can Med Assoc J 92: 574-575, 1965 123. Sugarman GI: Chondrodysplasia punctata (rhizomelic type): Case report and pathologic findings. Birth Defects 10(12):334-340, 1974 124. Levine RE, Synder AA, Sugarman GI: Ocular involvement in chondrodysplasia punctata. Am J Ophthalmol 77:851-859, 1974 125. Briggs JN, Emery JL, Illingworth RS: Congenital stippled epiphyses. Arch Dis Child 28:209-212, 1953 126. Coughlin EJ, Guare HT, Moskowitz AJ: Chondrodystrophia calcificans congenita. J Bone Jt Surg 32A:938-942, 1950 127. Visezkul C, Opitz JM, Spranger JW, Hartmann HA, Gilbert EF: Pathology of chondrodysplasia punctata rhizomelic type. Birth Defects 10(12):327-333, 1974 128. Jarousse V, Lerat M, Sorin A, Kerneis JP, Hervouet F, Cavellat J: A propos d'un cas de maladie cong6nitale des epiphyses pointillees. J Radiol Electrol 40:99-100, 1959 129. Silverman FN: Discussion on the relation between stippled epiphyses and the multiplex form of epiphyseal dysplasia. Birth Defects 5(4):68-70, 1969 130. Ford GD, Schneider M, Brandon JR: Congenital stippled epiphyses. Pediatrics 8:380-392, 1951 131. Frank WW, Denny MB: Dysplasia epiphysialis punctata. J Bone Joint Surg [Br] 36:118-122, 1954 132. Karlen AG, Cameron JAP: Dysplasia epiphysialis punctata. J Bone Joint Surg [Br] 39:293-301, 1957 133. Raap G: Chondrodystrophia calcificans congenita. Am J Roentgenol 49:77-82, 1943 134. Maroteaux P, Spranger J, Opitz JM, Kucera J, Lowry RB, Schimke RN, Kagan SM: Le syndrome campomelique. Presse Med 79:1157-1162, 1971 135. Bianchine JW, Risemberg HM, Kanderian SS, Harrison HE: Camptomelic dwarfism. Lancet 1:1017-1018, 1971 136. Opitz JM, Feingold M, Bull MJ, Spranger JW: The campomelic syndrome: comments. Birth Defects 10(9):97-99, 1974 137. Currarino G: Hypophosphatasia,32 pp 469-494

848

138. 139. 140. 141. 142. 143. 144. 145. 146.

147. 148.

149. 150. 151.

152. 153. 154.

155. 156. 157. 158. 159. 160.

161. 162.

SILLENCE ET AL


Khajavi A, Lachman R, Rimoin D, Schimke RN, Dorst J, Handmaker S, Ebbin A, Perreault G: Heterogeneity in the campomelic syndromes. Radiology 120:641647, 1976 Khajavi A, Lachman RS, Rimoin DL, Schimke RN, Dorst JP, Ebbin AJ, Handmaker S, Perreault G: Heterogeneity in the campomelic syndromes: Long and short bone varieties. Birth Defects 12(6):93-100, 1976 Rogers JG, Cranley RE, Dorst JP, Levin LS, Williams BR: A variant of campomelia. Birth Defects 11(6):119-125, 1975 Lee FA, Isaacs H, Strauss J: The "campomelic" syndrome. Am J Dis Child 124:485-496, 1972 Hoefnagel D, Wurster D, Carey D, Harris GJ, Pilliod J: Camptomelic dwarfism. Lancet 1:1068, 1972 Cremin BJ, Orsmond G, Beighton P: Autosomal recessive inheritance in camptomelic dwarfism. Lancet 1:488-489, 1973 Becker MH, McCarthy JS, Genieser NB, Converse JM: A proposed classification for craniofacial malformations. Birth Defects 10(7):171-175, 1974 Storer J, Grossman H: The campomelic syndrome. Radiology 111:673-681, 1974 St{ive A, Wiedemann H: Congenital bowing of the long bones in two sisters. Lancet 2:495, 1971 Thurmon TF, DeFraites EB, Anderson EE: Familial camptomelic dwarfism. J Pediatr 83:841-843, 1973 Langer LO, Jr, Baumann PA, Gorlin RJ: Achondroplasia. Am J Roentgenol 100:12-26, 1967 Silverman FN: Achondroplasia,32 pp 94-124 Zellweger H, Taylor B: Genetic Aspects of Achondroplasia. Lancet 85:8-16, 1965 Murdoch JL, Walker BA, Hall JG, Abbey H, Smith KK, McKusick VA: Achondroplasia. A genetic and statistical survey. Ann Hum Genet 33:227-244, 1970 Rimoin DL, Hughes GN, Kaufman RL, Rosenthal RE, McAlister WH, Silberberg R: Enchondral ossification in achondroplastic dwarfism. N EngI J Med 283:728735, 1970 Ponseti IV: Skeletal growth in achondroplasia. J Bone Joint Surg (Am) 52:701716, 1970 Stanescu V, Bona C, Ionescu V: The tibial growing cartilage biopsy in the study of growth disturbances. Acta Endocrinol 64:577-601, 1970 McKusick VA, Kelly TE, Dorst JP: Observations suggesting allelism of the achondroplasia and hypochondroplasia genes. J Med Genet 10:11-16, 1973 Walker BA, Scott CI, Hall JG, Murdock JL, McKusick VA: Diastrophic dwarfism. Medicine 51 :41-59, 1972 Stover CN, Hayes JT, Holt JF: Diastrophic dwarfism. Am J Roentgenol 89:914922, 1963 Taybi H: Diastrophic dwarfism. Radiology 80:1-10, 1963 Langer LO Jr: Diastrophic dwarfism in early infancy. Am J Roentgenol 93:399404, 1965 Wilson DW, Chrispin AR, Carter CO: Diastrophic dwarfism. Arch Dis Child 44:48-58, 1969 Taber P, Freedman S, Lackey DA: Diastrophic dwarfism,32 pp 152-166 Freedman SI, Taber P, Hollister DW, Rimoin DL: A lethal form of diastrophic dwarfism. Birth Defects 10(12):43-49, 1974

163. 164.

HollisterDW, Lachman RS: Diastrophicdwarfism. ClinOrthop 114:61-69,1976 Horton WA, Rimoin DL, Lachman RS, Scovby F, Hollister DL, Spranger J, Scott CI, Hall JG: Phenotypic variability of diastrophic dysplasia. J Pediatr 93:609-613,

165.

1978 Horton WA, Rimoin DL: Diastrophic dwarfism: a histochemical and ultrastructural study of the endochondral growth plate. Pediatr Res (In press)


SKELETAL DYSPLASIAS

849

166. Scheck M, Parker J, Daentl D: Hyaline cartilage changes in diastrophic dwarfism. Virchows Arch (Pathol Anat) 378:347-359, 1978 167. Gefferth K: Metatropic dwarfism,32 pp 137-151 168. Maroteaux P: Spondyloepiphyseal dysplasias amd metatropic dwarfism. Birth Defects 5(4):35-44, 1969 169. Jenkins P, Smith MB, McKinnell JS: Metatropic dwarfism. Br J Radiol 43:561565, 1970 170. Ellis RWB, van Creveld S: A syndrome characterized by ectodermal dysplasia, polydactyly, chondro-dysplasia and congenital morbus cordis: Report of three cases. Arch Dis Child 15:65-84, 1940 171. McKusick VA, Eldridge R, Hostetler JA, Egeland JA: Dwarfism in the Amish. Trans Assoc Am Physicians 77:151-168, 1964 172. J6quier S, Dunbar JS: The Ellis-van Creveld syndrome,32 pp 167-183 173. Le Marec B, Passarge E, Dellenbach P, Kerisit J, Signargout J, Ferrand B, Senecal J: Les formes neonatales lethales de la dysplasie chondro-ectodermique: Apropos de cinq observations. Ann Radiol 16:19-26, 1973 174. Kozlowski K, Szmigiel C, Barylak A, Stopyrowa M: Difficulties in differentiation between chondroectodermal dysplasia (Ellis-van Creveld syndrome) and asphyxiating thoracic dystrophy. Australas Radiol 16:401-410, 1972 175. Metrakos JD, Fraser FC: Evidence of a hereditary factor in chondroectodermal dysplasia (Ellis-van Creveld syndrome). Am J Hum Genet 6:260-269, 1954 176. Smith HL, Hand AM: Chondoectodermal dysplasia (Ellis-van Creveld syndrome): Report of two cases. Pediatrics 21:298-307, 1958 177. Uehlinger E: Pathologische Anatomie der Chondro-ektodermalen Dysplasia Ellisvan Creveld. Schweiz Z Pathol Bakt 20:754-766, 1957 178. Pirnar T, Neuhauser EBD: Asphyxiating thoracic dystrophy of the newborn. Am J Roentgenol 98:358-364, 1966 179. Jequier JC, Favreau-Ethier M, Gregorie H: Asphyxiating thoracic dysplasia,32 pp 184-210 180. Oberklaid F, Danks DM, Mayne V, Campbell P: Asphyxiating thoracic dysplasia: Clinical, radiological and pathological information on 10 patients. Arch Dis Child 52:758-765, 1977 181. Grushkin AB, Boluarte HJ, Cote ML, Effenhein IB: The renal disease of thoracic asphyxiant dystrophy. Birth Defects 10:44-50, 1974 182. Herdman RC, Langer LO: The thoracic asphyxiant dystrophy and renal disease. Am J Dis Child 116:192-201, 1968 183. Shokeir MHK, Houston CS, Awen CF: Asphyxiating thoracic chondrodystrophy: Association with renal disease and evidence for possible heterozygous expression. J Med Genet 8:107-112, 1971 184. Maroteaux P, Savart P: La dystrophie thoracique asphyxiante. etude radiologique et rapports avec le syndrome d'Ellis et van Creveld. Ann Radiol 7:332-338, 1964 185. Jeune M, Beraud C, Carron R: Dystrophic thoracique asphyxiante de caractere familial. Arch Fr Pediatr 12:886-891, 1955 186. Phillips SJ, Magsamen BF, Punnett HH, Kisternmacher ML, Campo RD: Fine structure of skeletal dysplasia as seen in pseudoachondroplastic spondyloepiphyseal dysplasia and asphyxiating thoracic dystrophy. Birth Defects 10:314-326, 1974 187. Williams BR, Cranley RE: Morphologic observations on four cases of SED congenita. Birth Defects 10(9):75-87, 1974 188. Spranger J: The epiphyseal dysplasias. Clin Orthop 114:46-60, 1976 189. Spranger J: Spondyloepiphyseal dysplasias. Birth Defects 11(6):177-182, 1975 190. Lachman RS, Rimoin DL, Hall JG, Kozlowski K, Langer LO, Scott CI, Spranger J: Difficulties in the classification of the epiphyseal dysplasias. Birth Defects 11(6):231-248, 1975 191. Kniest W: Zur Abgrenzung der Dysostosis enchondralis von der Chondrodys-

850

SILLENCE ET AL


trophie. Z Kinderheilkd 70:633-640, 1952 192. Spranger JW, Maroteaux P: Kniest disease. Birth Defects 10(12):50-56, 1974 193. Siggers CD, Rimoin DL, Dorst JP, Doty SB, Williams BR, Hollister DW, Silberberg R, Cranley RG, Kaufman RL, McKusick VA: The Kniest syndrome. Birth Defects 10:193-208, 1974 194. Lachman RS, Rimoin DL, Hollister DW, Dorst JP, Siggers DC, McAlister W, Kaufman RL, Langer LO: The Kniest syndrome. Am J Roentgenol Radium Ther Nucl Med 123:805-814, 1975 195. Rimoin DL, Siggers DC, Lachman RS, Silberberg R: Metatropic dwarfism, the Kniest syndrome and the pseudoachondroplastic dysplasias. Clin Orthop 114:7082, 1976 196. Horton WA, Rimoin DL: The Kniest dysplasia, a histochemical study of the growth plate. Pediatr Res (In press) 197. Waggener JD: Ultrastructure of benign peripheral nerve sheath tumors. Cancer 19:699-709, 1966 198. Kaitila I, Leisti JT, Rimoin DL: Mesomelic skeletal dysplasias. Clin Orthop 114:94-106, 1976 199. De la Chapelle A, Maroteaux P, Havu N, Granroth G: Une rare dysplasie osseuse lethale de transmission recessive autosomique. Arch Fr Pediatr 29:759-770, 1972 200. Fried K, Kalna N: Die mesomelischen Dysplasien. Radiol Diagn (Berl) 11:4491970 201. Herrman J, Opitz JM: The VSR syndrome: Studies of malformation syndromes of man XXXII. Birth Defects 10:277-239, 1974 202. Lowry RB: Congenital absence of the fibula and craniosynostosis in sibs. J Med Genet 9:227-229, 1972 203. Rupprecht E, Maintz U: Beitrag zum Krankheitsbild der angeborenen Verbiegung langer Ro5hrenknochen. Helv Paediatr Acta 28:467-476, 1973 204. Wegmann B: Eine neue mesomele Zwergwuchsform. Helv Paediatr Acta 27:267276, 1972 205. Waida RS, Shirlone DB, Dikshit MS: Recessively inherited costovertebral segmentation with mesomelia and peculiar facies (Covesdem syndrome): A new genetic entity? J Med Genet 15:123-127, 1978 206. Maroteaux P: Acromesomelic dwarfism,32 pp 563-565 207. Campailla E, Martinelli B: Deficit structurale con micromesomelia. Minerva Ortopedica 22:180-184, 1971 208. Kozlowski K: Hypochondroplasia,32 pp 238-249 209. Walker BA, Murdoch JL, McKusick VA, Langer LO, Beals RK: Hypochondroplasia. Am J Dis Child 122:95-104, 1971 210. Leri A, Weill J: Une affection congenitale et symetrijue du developpement osseux: La dyschondrosteose. Bull Soc Med Hop 53:1491-1494, 1929 211. Herdman RC, Langer LO, Good RA: Dyschondrosteosis: The most common cause of Madelung's deformity. J Pediatr 68:432-441, 1966 212. Silverman FN: Mesomelic dwarfism,32 pp 546-562 213. Sutcliffe J, Stanley P: Metaphyseal chondrodysplasias,32 pp 250-269 214. Kozlowski K: Metaphyseal and spondylometaphyseal chondrodysplasias. Clin Orthop 114:83-93, 1976 215. Jansen M: UJber atypische Chondrodystrophie (Achondroplasie) und Ober eine noch nicht beschriebene angeborene Wachstumsstorung des Knochensystems: Metaphysare Dysostosis. Z Orthop Chir 61:253-286, 1934 216. DeHaas WHD, DeBoer W, Griffloen F: Metaphyseal dysostosis. A late follow-up of the first reported case. J Bone Joint Surg [Br] 51:290-299, 1969 217. Gram PB, Fleming JL, Frame B, Fine G: Metaphyseal chondrodysplasia of Jansen. J Bone Joint Surg [Am] 41:951-959, 1959 218. Lenz WD, Holt JF: Discussion: Murk Jansen type of metaphyseal dysostosis. Birth Defects 5(4):71-75, 1969


SKELETAL DYSPLASIAS

851

219. Ozonoff MB: Metaphyseal dysostosis of Jansen. Radiology 93:1047-1050, 1969 220. Schmid F: Beitrag zur Dysostosis Enchondralis Metaphysaria. Monatsschr Kinderheilkd 97:393-397, 1949 221. Schmidt BJ, Becak W, Becak ML, Soibleman I, Da Silva Queiroz A, Lorga AP, Secaf F, Antonio CF, deAndrade Carvalho A: Metaphyseal dysostosis. J Pediatr 63:106-112, 1963 222. Dent CE, Normand ICS: Metaphyseal dysostosis, type Schmid. Arch Dis Child 39:444-454, 1964 223. McKusick VA, Eldridge R, Hostetler JA, Ruangwit U, Egeland JA: Dwarfism in the Amish: II. Cartilage-hair hypoplasia. Bull Hopkins Hosp 116:285-326, 1965 224. Ray HC, Dorst JP: Cartilage-hair hypoplasia,32 pp 270-298 225. Lowry RB, Wood BJ, Birkbeck JA, Padwick PH: Cartilage-hair hypoplasia: A rare and recessive cause of dwarfism. Clin Pediatr 9:44-46, 1970 226. Coupe RL, Lowry RB: Abnormality of the hair in cartilage-hair hypoplasia. Dermatologica 141:329-334, 1970 227. Lux SE, Johnston RB, August CS, Say B, Penschaszadeh VB, Rosen FS, McKusick VA: Chronic neutropenia and abnormal cellular immunity in cartilage-hair hypoplasia. N Engl J Med 282:231-236, 1970 228. Aleck K, Romeo G, Miller M, Rimoin D, Galant S: Immunologic studies in cartilage-hair hypoplasia (abstr). Clin Res 26(2):192, 1978 229. Schwachman H, Diamond LK, Oski FA, Khaw KT: The syndrome of pancreatic insufficiency and bone marrow dysfunction. J Pediatr 65:645-663, 1964 230. Taybi H, Mitchell AD, Friedman GD: Metaphyseal dysostosis and the associated syndrome of pancreatic insufficiency and blood disorders. Radiology 93:563-571, 1969 231. Pringle EM, Young WF, Haworth EM: Syndrome of pancreatic insufficiency, blood dyscrasia and metaphyseal dysplasia. Proc R Soc Med 61:776-777, 1968 232. Shmerling DH, Prader A, Hitzig WH, Giedion A, Hadorn B, Kflhni M: The syndrome of exocrine pancreatic insufficiency, neutropenia, metaphyseal dysostosis and dwarfism. Helv Paediatr Acta 24:547-575, 1969 233. Alexander WJ, Dunbar JS: Unusual bone changes in thymic alymphoplasia. Ann Radiol 11:389-394, 1968 234. Fulginiti VA, Hathaway WE, Pearlman DS, Kempe CH: Agammaglobulinaemia and achondroplasia. Br Med J 2:242, 1967 235. Gatti RA, Platt N, Pomerance HH, Hong R, Langer LO, Kay HEM, Good RA: Hereditary lymphopenic agammaglobulinemia associated with a distinctive form of short-limbed dwarfism and ectodermal dysplasia. J Pediatr 75:675-684, 1969 236. Nahmias AJ, Griffith D, Salsbury C, Yoshida K: Thymic aplasia, with lymphopenia, plasma cells, and normal immunoglobulins. JAMA 201:729-734, 1967 237. Cedarbaum SD, Kaitila I, Rimoin DL, Stiehm ER: The chondro-osseous dysplasia of adenosine deaminase deficiency with severe combined immunodeficiency. J Pediatr 89:737-742, 1976 238. Kaitila I, Rimoin DL, Cedarbaum SD, Stiehm ER, Lachman RS: Chondro-osseous histopathology in adenosine deaminase deficient combined immunodeficiency disease. Birth Defects 12:115-121, 1976 239. Cooper RR, Ponseti IV: Metaphyseal dysostosis: Description of an ultrastructural defect in the epiphyseal plate chondrocytes. J Bone Joint Surg [Am] 55:485-495, 1973 240. Cooper RR, Pedrini-Mille A, Ponseti IV: Metaphyseal dysostosis: A rough surfaced endoplasmic reticulum storage defect. Lab Invest 28:119-125, 1973 241. Kikuchi S, Hasue M, Watanabe M, Hasebe K: Metaphysial dysostosis (Jansen type): Report of a case with long follow-up. J Bone Joint Surg [Br] 58:102-106, 1976 242. Spycher MA, Giedion A, Shmerling DH, Ruttner JR: Electron microscopic examination,of cartilage in the syndrome of exocrine pancreatic insufficiency, neutro-

852

SILLENCE ET AL


penia, metaphyseal dysostosis and dwarfism. Helv Paediatr Acta 29:471-479, 1974 243. Kozlowski K, Maroteaux P, Spranger J: La dysostose spondylo-m6taphysaire. Presse Med 75:2769-2774, 1967 244. Fairbank HAT: Dysplasia epiphysealis multiplex. Proc R Soc Med 39:315-317, 1946 245. Fairbank T: Dysplasia epiphysialis multiplex. Br J Surg 34:225-232, 1947 246. Ribbing S: Studien Ober hereditire, multiple Epiphysenstorungen. Acta Radiol 34 (Suppl):1-107, 1937 247. Juberg RC, Holt JF: Inheritance of multiple epiphyseal dysplasia, tarda. Am J Hum Genet 20:549-563, 1968 248. Hunt DD, Ponseti IV, Pedrini-Mille A, Pedrini V: Multiple epiphyseal dysplasia in two siblings. J Bone Joint Surg [Am] 49:1611-1627, 1967 249. Watt JK: Multiple epiphyseal dysplasia: A report of four cases. Br J Surg 39:533535, 1952 250. Waugh W: Dysplasia epiphysialis multiplex in three sisters. J Bone Joint Surg [Br] 34:82-87, 1952 251. Weaver DD, Otter M, Colyer RA, Jackson CE: Juberg-Holt type recessive multiple epiphyseal dysplasia tarda in an Amish family. Proc Am Soc Hum Genet: 71A, 1978 252. Jacobs P: Multiple epiphyseal dysplasia,32 pp 309-324 253. Barrie H, Carter C, Sucliffe J: Multiple epiphyseal dysplasia. B Med J 2:133-137, 1958 254. Monty CP: Familial Perthes' disease resembling multiple epiphyseal dysplasia. J Bone Joint Surg [Br] 44:565-568, 1962 255. Kozlowski K, Lipska E: Hereditary dysplasia epiphysealis multiplex. Clin Radiol 18:330-336, 1967 256. Bona C, Stanescu V, Ionescu V: Histochemical studies on tibial growing cartilage in polyepiphyseal dysplasia (Fairbank disease, Mflller-Ribbing-Krankeit). Acta Histochem 21:284-298, 1965 257. Stickler GB, Maher FT, Hunt JC, Burke EC, Rosevear JW: Familial bone disease resembling rickets (hereditary metaphyseal dysostosis). Pediatrics 29:996-1004, 1962 258. Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG, Steinberg, AG, Ward LE: Hereditary progressive arthro-ophthalmopathy. Mayo Clin Proc 40:433-455, 1965 259. Stickler GB, Pugh DG: Hereditary progressive arthro-ophthalmopathy: II. Additional observation on vertebral abnormalities, a hearing defect, and a report of a similar case. Mayo Clin Proc 42:495-500, 1967 260. Hussels IE: Arthro-ophthalmopathy, Birth Defects Atlas and Compendium. Edited by D Bergsma. Baltimore, Williams and Wilkins 1973, pp 188-189 261. Opitz JM, France T, Herrmann J, Spranger JW: The Stickler syndrome. N Engl J Med 286:546-547, 1972 262. Schreiner RL, McAlister WH, Marshall RE, Shearer WT: Stickler syndrome in a pedigree of Pierre Robin syndrome. Am J Dis Child 126:86-90, 1973 263. Hall JG, Dorst JP: Four types of pseudo-achondroplastic spondylo-epiphyseal dysplasia (SED). Birth Defects 4(5):242-259, 1969 264. Rupprecht E, Purath W: Pseudoachondroplastic dysplasia,82 pp 566-578 265. Hall JG: Pseudoachondroplasia. Birth Defects 11(6):187-202, 1975 266. Hall JG: Personal communication, 1979 267. Cranley RE, Williams BR, Kopits SE, Dorst JP: Pseudoachondroplastic dysplasia: Five cases representing clinical roentgenographic and histologic heterogeneity. Birth Defects 11(6):205-215, 1975 268. Lindseth RE, Danigelis JA, Murray DG, Wray JB: Spondylo-epiphyseal dysplasia


SKELETAL DYSPLASIAS

853

(pseudoachondroplastic type): Case report with pathologic and metabolic investigations. Am J Dis Child 113:721-726, 1967 269. Phillips SJ: A rough endoplasmic reticulum storage disease in chondrocytes (abstr). Anat Rec 166:363, 1970 270. Maynard JA, Cooper RR, Ponseti IV: A unique rough surfaced endoplasmic reticulum inclusion in pseudoachondroplasia. Lab Invest 26:40-44, 1972 271. Cooper RR, Ponseti IV, Maynard JA: Pseudoachondroplastic dwarfism: A rough surfaced endoplasmic reticulum storage disorder. J Bone Joint Surg [Am] 55:475484, 1973 272. Bannerman RM: X-linked spondyloepiphyseal dysplasia tarda (SDT). Birth Defects 4(5):48-52, 1969 273. Poker N, Finby N, Archibald RM: Spondyloepiphysial dysplasia tarda. Four cases in childhood and adolescence, and some considerations regarding platyspondyly. Radiology 85:474-480, 1965 274. Specht EE: Spondyloepiphyseal dysplasia tarda: A case report. Clin Orthop 60:159-162, 1968 275. Byers PH, Holbrook KA, Hall JG, Bornstein P, Chandler JW: A new variety of spondyloepiphyseal dysplasia characterized by punctate corneal dystrophy and abnormal dermal collagen fibrils. Hum Genet 40:157-169, 1978 276. Dyggve HV, Melchior JC, Clausen J: Morquio-Ullrich's disease: An inborn error of metabolism? Arch Dis Child 37:525-534, 1962 277. Clausen J, Dyggve HV, Melchior JC: Mucopolysaccharidosis: Paper electrophoretic and infra-red analysis of the urine in gargoylism and Morquio-Ullrich's disease. Arch Dis Child 38:364-374, 1963 278. Kaufman RL, Rimoin DL, McAlister WH: The Dyggve-Melchior-Clausen syndrome. Birth Defects 7(1):144-149, 1971 279. Spranger J, Maroteaux P, Der Kaloustian VM: The Dyggve-Melchior-Clausen syndrome. Pediatr Radiol 114:415-421, 1975 280. Murdoch JL, Walker BA: A "new" form of spondylometaphyseal dysplasia. Birth Defects 5(4):368-370, 1969 281. Diamond LS: 0. Spondylometaphyseal dysplasia (Brazilian type). Birth Defects 10(12):412-415, 1974 282. Schwartz 0, Jampel RS: Congenital blepharophimosis associated with an unique generalized myopathy. Arch Opthal 68:52-57, 1962 283. Merev T, Porter IH, Hug G: Myotonia, shortness of stature and hip dysplasia: Schwartz-Jampel syndrome. Am J Dis Child 117:470-478, 1969 284. Huttenlocher PR, Landwirth J, Hanson V, Gallagher BB, Beusch K: Osteochondromuscular dystrophy: A disorder manifested by multiple skeletal deformities, myotonia and dystrophic changes in muscle. Pediatrics 44:945-958, 1969 285. Saadat M, Mokfi H, Vakil H, Ziai M: Schwartz syndrome: Myotonia with blepharophimosis and limitation of joints. J Pediatr 81:348-350, 1972 286. Kozlowski K, Wise G: Spondylo-epi-metaphyseal dysplasia with myotonia: A radiographic study. Radiol Diag 15:817-824, 1974 287. Fowler WM, Layzer RB, Taylor RG, Eberle ED, Sims GE, Munsat TL, Philippart M, Wilson BW: The Schwartz-Jampel syndrome: Its clinical, physiological and histological expressions. J Neurol Sci 22:127-146, 1974 288. Rask MR: Morquio-Brailsford osteochondrodystrophy and osteogenesis imperfecta: Report of a patient with both conditions. J Bone Joint Surg [Am] 45:561-570,

1963

289. Sensenbrenner JA, Dorst JP, Hungerford DS: S. Parastremmatic dwarfism. Birth Defects 10(12):425-429, 1974 290. Giedion A: Acrodysplasias,32 pp 325-345

854

SILLENCE ET AL


291. Brighton CT: Structure and function of the growth plate. Clin Orthop 136:22-32, 1978 292. Bagnall KM, Harris PF, Jones PRM: A radiographic study of the development of ossification in the shafts of limb long bones in the human male and female fetus (abstr). J Anat 124:493, 1977 293. Bagnall KM, Harris PF, Jones PRM: A radiographic study of the human fetal spine: 2. The sequence of development of ossification centres in the vertebral column. J Anat 124:791-802, 1977 294. Caffey J, Silverman FN: Pediatric X-ray Diagnosis. Chicago, Year Book Medical Publishers, 1967 295. Dearden LC, Bonucci E and Cuicchio M: An investigation of ageing in human costal cartilage. Cell Tiss Res 152:305-337, 1974

Acknowledgments We wish to thank R. Hamilton, C. Carpentier, L. Shimono, and Nina Dockery for their technical assistance in this project; Dr. Ruth Silberberg for her collaboration in the ultrastructural studies; our many clinical colleagues throughout the world who contributed biopsy material used in these studies; and T. Armstrong and E. Bruce for preparation of the manuscript.

Appendix: Second International Nomenclature of Constitutional Diseases 9f Bone (May 1977) OSTEOCHONDRODYSPLASIAS Abnormalities of Cartilage and/or Bone Growth Development 1. Defects of Growth of Tubular Bones and/or Spine A. Identifiable at birth 1. Achondrogenesis Type I (Parenti-Fraccaro) 2. Achondrogenesis Type II (Langer-Saldino) 3. Thanatophoric dysplasia 4. Thanatophoric dysplasia with cloverleaf skull 5. Short-ribpolydactyly syndrome Type I (Saldino-Noonan) (perhaps several forms) 6. Short-ribpolydactyly syndrome Type II (Majewski) 7. Chondrodysplasia punctata a. Rhizomelic form b. Dominant form c. Other forms Exclude: symptomatic stippling in other disorders (eg, Zellweger syndrome, Warfarin embryopathy) 8. Campomelic dysplasia 9. Other dysplasias with congenital bowing of long bones (several forms) 10. Achondroplasia 11. Diastrophic dysplasia 12. Metatropic dysplasia (several forms)


SKELETAL DYSPLASIAS

855

13. Chondroectodermal dysplasia (Ellis-van Creveld) 14. Asphyxiating thoracic dysplasia (Jeune) 15. Spondyloepiphyseal dysplasia congenita a. Spranger-Wiedemann type b. Other forms (see B, 11 and 12) 16. Kniest dysplasia 17. Mesomelic dysplasia a. Nievergelt type b. Langer type (probable homozygous dyschondrosteosis) c. Robinow type d. Rheinardt type e. Others 18. Acromesomelic dysplasia 19. Cleidocranial dysplasia 20. Larsen syndrome 21. Otopalatodigital syndrome B. Identifiable in later life 1. Hypochondroplasia 2. Dyschondrosteosis 3. Metaphyseal chondrodysplasia, Jansen type 4. Metaphyseal chondrodysplasia, Schmid type 5. Metaphyseal chondrodysplasia, McKusick type 6. Metaphyseal chondrodysplasia with exocrine pancreatic insufficiency and cyclic neutropenia 7. Spondylometaphyseal dysplasia a. Kozlowski type b. Other forms 8. Multiple epiphyseal dysplasia a. Fairbanks type b. Other forms 9. Arthro-ophthalmopathy (Stickler) 10. Pseudoachondroplasia a. Dominant b. Recessive 11. Spondyloepiphyseal dysplasia tarda 12. Spondyloepiphyseal dysplasia, other forms (see A, 15) 13. Dyggve-Melchior-Clausen dysplasia 14. Spondyloepimetaphyseal dysplasia (several forms) 15. Myotonic chondrodysplasia (Catel-Schwartz-Jampel) 16. Parastremmatic dysplasia 17. Trichorhinophalangeal dysplasias

856

SILLENCE ET AL


18. Acrodysplasia with retinitis. pigmentosa and nephropathy (Saldino-Mainzer) 11. Disorganized Development of Cartilage and Fibrous Components of Skeleton 1. Dysplasia epiphysealis hemimelica 2. Multiple cartilagenous exostoses 3. Acrodysplasia with exostoses (Giedion-Langer) 4. Enchondromatosis (Ollier) 5. Enchondromatosis with hemangioma (Maffucci) 6. Metachondromatosis 7. Fibrous dysplasia (Jaffe-Lichtenstein) 8. Fibrous dysplasia with skin pigmentation and precocious puberty

(McCune-Albright) 9. Cherubism (familial fibrous dysplasia of the jaws) 10. Neurofibromatosis 111. Abnormalities of Density of Cortical Diaphyseal Structure and/or Metaphyseal Modeling 1. Osteogenesis imperfecta congenita (several forms) 2. Osteogenesis imperfecta tarda (several forms) 3. Juvenile idiopathic osteoporosis 4. Osteoporosis with pseudoglioma 5. Osteopetrosis with precocious manifestations 6. Osteopetrosis with delayed manifestations (several forms) 7. Pyknodysostosis 8. Osteopoikilosis 9. Osteopathia striata 10. Melorheostosis 11. Diaphyseal dysplasia (Camurati-Engelmann) 12. Craniodiaphyseal dysplasia 13. Endosteal hyperostosis a. Autosomal dominant (Worth) b. Autosomal recessive (Van Buchem) 14. Tubular stenosis (Kenny-Caffey) 15. Pachydermoperiostosis 16. Osteodysplasty (Melnick-Needles) 17. Frontometaphyseal dysplasia 18. Craniometaphyseal dysplasia (several forms) 19. Metaphyseal dysplasia (Pyle) 20. Sclerosteosis 21. Dysosteosclerosis 22. Osteoectasia with hyperphosphatasia

SKELETAL DYSPLASIAS


857

Dv'sosT osEs Malformnation of Individual Bones, Singly or in Combination I. Dysostoses with Cranial and Facial Involvement 1. Craniosynostosis (several forms) 2. Craniofacial dysostosis (Crouzon) 3. Acrocephalosyndactyly (Apert) and others 4. Acrocephalopolysyndactyly (Carpenter) and others 5. NMandibulofacial dysostosis a. Treacher-Collins, Franceschetti types b. Other forms 6. Oculomandibulofacial syndrome (Hallermann-Streiff-Francois) 7. Nevoid basal-cell carcinoma syndrome II. Dysostoses with predominant axial involvement 1. Vertebral segmentation defects (including Klippel-Feil) 2. Cervicooculoacoustic syndrome (Wildervanck) 3. Sprengel anomaly 4. Spondylocostal dysostosis a. Dominant forms b. Recessive forms 5. Oculovertebral syndrome (Weyers) 6. Osteo-onychodysostosis 7. Cerebrocostomandibular syndrome III. Dysostoses with predominant involvement of extrenmities 1. Acheiria 2. Apodia 3. Ectrodactyly syndrome 4. Aglossia-adactyly syndrome 5. Congenital bowing of long bones (several forms) (see also Osteochondrodysplasias) 6. Familial radioulnar synostosis 7. Brachydactyly (several forms) 8. Symphalangism 9. Polydactyly (several forms) 10. Syndactyly (several forms) 11. Polysyndactyly (several forms) 12. Camptodactyly 13. Poland syndromre 14. Rubinstein-Taybi syndrome 15. Pancytopenia-dysmelia syndrorne (Fanconi) 16. Thromb)ocytopenia-radial-aplasia syndrome 17. Orodigitofacial syndrome

858


SILLENCE ET AL

18. 19. 20. 21. 22. 23.

a. Papillon-Leage type b. Mohr type Cardiomelic syndrome (Holt-Oram and others) Femoral facial syndrome Multiple synostoses (includes some forms of symphalangism) Scapuloiliac dysostosis (Kosenow-Sinios) Hand foot genital syndrome Focal dermal hypoplasia (Goltz) IDIOPATHIC OSTEOL1YSES

1. Phalangeal (several forms) 2. Tarsocarpal a. Including Francois form and others b. With nephropathy 3. M ulticentric a. Hajdu-Cheney form b. Winchester form c. Other forms

CIIRONIOSOMNAL ABERRATI IONS Primary Metabolic Abnornmalities I. Calcium and/or phosphorus 1. Hypophosphatemic rickets 2. Pseudodeficiency rickets (Prader, Royer) 3. Late rickets (McCance) 4. Idiopathic hypercalcuria 5. Hypophosphatasia (several forms) 6. Pseudohypoparathyroidism (normocalcemic and hypocalcemic forms, including acrodysostosis) II. Complex carbohydrates 1. Mucopolysaccharidosis Type I (alpha-i -iduronidase deficiency) a. Hurler form b. Scheie form c. Other forms 2. Mucopolysaccharidosis Type II (Hunter) (sulfoiduronate sulfatase deficiency) 3. M ucopolysaccharidosis Type III (Sanfilippo) a. Type A (heparin sulfamidase deficiency) b. Type B (N-acetyl-alpha-glucosaminadase deficiency) 4. Mucopolysaccharidosis Type IV (Morquio) (N-acetyl-

galactosamine-6-sulfate-sulfatase deficiency)


III. IV.

V. VI.

SKELETAL DYSPLASIAS

859

5. Mucopolysaccharidosis Type VI (Maroteaux-Lamy) (aryl-sulfatase B deficiency) 6. Mucopolysaccharidosis Type VI (beta-glucuronidase deficiency) 7. AspartylgIucosaminuria (aspartyl-glucosaminidase deficiency) 8. Mannosidosis (alpha-mannosidase deficiency) 9. Fucosidosis (alpha-fucosidase deficiency) 10. GM1-gangliosidoses (beta-galactosidase deficiency) 11. Multiple sulfatase deficiency (Austin, Thieffry) 12. Neuraminidase deficiency (formerly mucolipidosis I) 13. Mucolipidosis II 14. Mucolipidosis III Lipids 1. Niemann-Pick disease 2. Gaucher's disease Nucleic acids 1. Adenosine-deaminase deficiency and others Aminoacids 1. Homocystinuria and others Metals 1. Menkes' kinky hair syndrome and others

860

SILLENCE ET AL


[Illustrations follow]

0< -

..

. ,-

e

-~ -

*

AV. S

J

-

,

-

fl

-

-+

s ,

.... a~~~~~~~~~~~~tk,

Figure 3A-Achondrogenesis 11 (Langer-Saldino). Zone of reserve chondrocytes showing hypercellular cartilage with enlarged chondrocytes. Newborn. (PAS/alcian blue, X80) B-Achondrogenesis 11 (Langer-Saldino). Zones of reserve, proliferative and hypertrophic chondrocytes and zone of chondro-osseous transformation showing hypercellularity with complete disorganization of endochondral ossification. Newborn. (PAS and alcian blue, X40) C-Thanatophoric dysplasia. Growth plate from humerus showing ballooned proliferative and hypertrophic zone chondrocytes and disorganized endochondral ossification. Newborn. (H&E, X40) D-Thanatophoric dysplasia with cloverleaf skull deformity. Growth plate from femur showing area of fibrous dysplasia and bone arising directly from this fibrous matrix. Newborn. (Trichrome, X40) (All with a photographic reduction of 3%)

'#R .4

t#'

*

3

*.

r

w

t

a:::

.:fsr

s 'b

*

S.

41.

^ v~w* £ * *w ..

J *1 .,

ii9._4L *'' ;?'

.l w Iti1

,j,! tC

459

4 0

w: :S;R

--

-

or

Sm: *

Figure 4A-Short-rib-polydactyly dysplasia (Saldino-Noonan). Growth plate from femur showing B-Chondrodysplasia punctata disorganized column formation. Newborn. (Trichrome, X40) (rhizomelic type). Zone of reserve chondrocytes from tibia showing fibrous dysplasia, adipocytes and C-Campomelic dysdysplastic calcification. Male aged 5 months. (Trichrome, decalcified, x40) plasia (long-limbed variety). Tibial growth plate showing normal endochondral ossification. Newborn. Apex of tibial bowvariety). D-Campomelic dysplasia (long-limbed (Trichrome, decalcified, X40) ing showing dense fibrous osseous trabeculae orientated at right angles to shaft and pointing towards apex. Newborn. (Trichrome, decalcified, X40) (All with a photographic reduction of 1%)

14

Figure 5A-Achondroplasia. Costochondral junction growth plate showing relatively normal endochondral ossification. Male aged 4 years. (Trichrome, X40) B-Homozygous achondroplasia. Iliac crest growth plate showing hypercellular proliferative and hypertrophic zones with disorganized endochondral ossification and prominent chondrocyte lacunas. (Trichrome, X40) CDiastrophic dysplasia. Iliac crest, zone of reserve chondrocytes Newborn. showing clumping of reserve-zone chondrocytes with 3-4 cells per lacuna and fibrous dysplastic changes in the matrix. Female, aged 14 years. (Trichrome, X40) D-Diastrophic dysplasia. Iliac crest. Chondrocyte in zone of reserve chondrocytes showing a large lipid vacuole and large collagen fiber aggregates in the chondrocyte lacuna forming a partial corona. Female aged 61/2 years. (Uranyl acetate and Reynolds' lead citrate, X5000) (All with a photographic reduction of 3%)

.9

~~~~~~~~~~~~~~~~~~~h

,j t

,f,.

A

~

,!

t ~~

~ ~ 4r.~

t

A

+

X

~

_

+

: ,!s 4; ;~~~

~

.

of dysplastic cartilage Figure 6A-Metatropic dysplasia. Iliac crest growth plate showing islandsB-Metatropic dysplasia. between primary osseous trabeculas. Male aged 6 years. (H&E, X40) Iliac crest chondrocyte showing vacuolation. Male aged 6 years. (Uranyl acetate and Reynolds' lead abnormally showing C-Chondroectodermal dysplasia. Iliac crest growth plate citrate, x5000) (Trilarge chondrocyte lacunas and areas of fibrous dysplasia in the matrix. Male aged 16 years. growth plate showing D-Asphyxiating thoracic dysplasia. Costochondral junction chrome, X80) irregular column formation with broad irregularly shaped cartilagenous trabeculas. Newborn. (Trichrome, X40) (All with a photographic reduction of 3%)

0 ... ..

.

I

4ps At

It, If_W

Figure 7A-Spondyloepiphyseal dysplasia congenita (Spranger-Wiedemann). Chondrocyte showing abnormal dilatation of endoplasmic reticulum containing an homogeneous granular material. Upper proliferative zone. Male aged 1 year. (Uranyl and Reynolds' lead citrate, X7600) B-Kniest dysplasia. Growth plate from costochondral acetate junction disorganization of cells and matrix with Swiss-cheese appearance. Male aged 6 years. (PAS showing and alcian blue, X20) C-Kniest dysplasia. Chondrocyte from upper proliferative zone showing dilated rough endoplasmic reticulum. Male aged 6 years. (Uranyl acetate and Reynolds' lead citrate, X7000) D-Kniest dysplasia. Cartilage matrix showing fibrous long spacing collagen. Male aged 6 years. (Uranyl acetate and Reynolds' lead citrate, X18,000) (All with a photographic reduction of 1%)

:

a-S

S ; 2

w~~~~~~~~~~~~

-iB ~~~~Z X D0 g r ;F ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

clusters of chondrocytes Figure 8A-Metaphyseal chondrodysplasia (Jansen). Growth plate showing B-Adenosine deaminase separated by wide zones of matrix. Male aged 1 year. (Trichrome, X40) of normal deficiency. Growth plate showing clusters of chondrocytes with almost complete absence C-Multiple epiphyseal dysplasia (Fairbanks). chondrocyte maturation, Newborn. (H&E, X80) D-Multiple reserve chondrocytes showing inclusions. Female aged 2 years. (Trichrome, X80) of matrix epiphyseal dysplasia (presumed autosomal recessive) showing abnormal condensation reduction around chondrocytes. Female aged 2 years. (Toluidine blue, x80) (All with a photographic of 2%)

N.

.."

8~ ~ .'Xw:.S '

...(. .: p..

I:

* '4

s_ . : : ...

_A%

:

m

.

-. *

,.

.-'t .It

*:~..

.1...

...

p0m

..

''

404

.... .V

Figure 9A-Pseudoachondroplasia. Iliac crest growth-plate cartilage showing large intracytoplasmic inclusions in chondrocytes. Female aged 3 years, mildly affected. (Trichrome, x80) B-Pseudoachondroplasia. Iliac crest growth-plate cartilage showing disruption of endochondral ossification with clumping of chondrocytes into single large lacunas. Female aged 6 years, severely affected. (Trichrome, X40) C-Pseudoachondroplasia. Iliac crest zone of proliferative chondrocytes showing intracytoplasmic inclusions. Female aged 3 years, mildly affected. (Uranyl acetate and Reynolds' lead citrate, X4500) D-Pseudoachondroplasia. Iliac crest. Chondrocyte showing typical inclusions in rough endoplasmic reticulum. Female aged 3 years. (Uranyl acetate and Reynolds' lead citrate, X29,000) (All with a photographic reduction of 1%)

lo

4~~~~~~~~~~~~~~~~~~~~~~~~~~f

*W .v .".1 ...?

||-iSfi

Figure 1OA-Dyggve-Melchior-Clausen dysplasia. Zone of reserve chondrocytes showing large foci of cells separated from surrounding clusters by fibrous matrix. Female aged 18 years. (Trichrome, B-Dyggve-Melchior-Clausen dysplasia, Iliac crest cartilage showing foci of necrotic chonX80) drocytes and cellular debris. Female aged 18 years. (Uranyl acetate and Reynolds' lead citrate, C-Spondyloepimetaphyseal dysplasia. Costochondral junction growth plate showing x7600) D-Spondyloepimetaphyseal dysplasia. relative hypocellularity. Male aged 8 years (H&E, x40) Iliac crest chondrocyte showing dilated rough endoplasmic reticulum. Male aged 8 years. (Uranyl acetate and Reynolds' lead citrate, X6200) (All with a photographic reduction of 3%)

Significant clinical benefits of molecular studies in the skeletal dysplasias.

Skeletal dysplasias.

Dermatoglyphs in skeletal dysplasias.

Immunopathologic and morphologic studies of skeletal muscle in Chagas' disease.

Guidelines for genetic skeletal dysplasias for pediatricians.

Skeletal Dysplasias: Growing Therapy for Growing Bones.

Morphologic studies for skeletal toxicity after prolonged ciprofloxacin therapy in two juvenile cystic fibrosis patients.

Genetic skeletal dysplasias: a guide to diagnosis and management.

Fetal skeletal dysplasias: sonographic indices associated with adverse outcomes.

The treatment of cervical dysplasias.

Skeletal Dysplasias That Cause Thoracic Insufficiency in Neonates: Illustrative Case Reports.

Rigid fixation improves outcomes of spinal fusion for C1-C2 instability in children with skeletal dysplasias.

Fetal skeletal dysplasias in a tertiary care center: radiology, pathology, and molecular analysis of 112 cases.

Transnasal US of the esophagus: preliminary morphologic and function studies.

[Advances in bone dysplasias].

The acro-osteolysis syndrome: Morphologic and biochemical studies.

The spontaneously diabetic Wistar rat. Metabolic and morphologic studies.

Ophthalmic manifestations of systemic diseases--part 2: metabolic, infections, granulomatoses, demyelination, and skeletal dysplasias.

Metabolic and morphologic studies in intraportal-islet-transplanted rats.

Chagasic cardiopathy. Immunopathologic and morphologic studies in myocardial biopsies.

The classification and registration of bone dysplasias.

Heparan Sulfate Cause Skeletal and Skin Dysplasias.

Collagen, genes and the skeletal dysplasias on the edge of a new era: a review and update.

Lymphatic vessel dysplasias.