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Review Article 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 821 Achondrogenesis I (Parenti-Fraccaro) 821 Achondrogenesis II (Larger-Saldino) 822 Thanatophoric Dvsplasia 823 Thanatophoric Dvsplasia With Cloverleaf Skull Deformity 824 Short-Rib-Polydactyly Syndromes 824 Short-Rib-Polydactyly Dysplasia I (SaldinoNoonan) 824 Short- Rib-Polydactyly Dysplasia II (Majewski) 825 Chondrodysplasia Punctata 825 Rhizomelic Chondrodysplasia Punctata 826 Conradi-HUlnermann Chondrodysplasia Punctata 826 Sex-Linked Chondrodysplasia Punctata 827 Campomelic Dysplasias 827 Long-Limbed Campomelic Dysplasia 827 Short-Limnbed Campomelic Dysplasia, Normocephalic Type 828 Short-Limbed Campomelic Dysplasia With Craniosynostosis 828 Achondroplasia 828 Homozygous Achondroplasia 829 Diastrophic Dysplasia 830 Metatropic Dysplasia 831 Chondroctodermal Dysplasia (Ellis-van Creveld Syndrome) 831 Asphyxiating Thoracic Dysplasia 832 Spondyloepiphyseal Dysplasias 833 Kniest Dysplasia 833 Mesomelic Dysplasias 834 Aeromesomelic Dysplasias 834 Skeletal Dysplasias Indentifiable in Later Life 835 Hypochondroplasia 835 Dyschondrosteosis 835 Metaphyseal Dysplasia 835 Spondylometaphyseal Dysplasias 837 Multiple Epiphyseal Dysplasias 837 Arthro-ophthalmopathy (Stickler) 838 Pseudoachondroplasia 838 Spondyloepiphyseal Dysplasia Tarda 839 Spondyloepiphyseal Dysplasia, Other Forms 840 Dyggve-Melchior-Clausen Syndrome 840 Spondyloepimetaphyeal Dysplasias 840 Myotonic Chondrodysplasia (Catel-Schwartz-Jampel) 841 Parastremmatic Dysplasia 841 Trichorhinophalangeal Dysplasias 841 Conclusion 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 dys- plasias, a heterogeneous group of disorders that consist of over 80 distinct conditions. Morphologic studies have added a further dimension to the delineation of these condi- tions, 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 electron- microscopic studies of growth-plate cartilage have provided new insights into the com- plexity of morphogenetic events in normal growth through the demonstration of mor- phologic 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 in- sight 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 regard- ing 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 de- fined,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 terminol- ogy. Two international meetings have been held, the first in 1969,283o the second in 1977,1 to formulate an acceptable nomenclature for constitu- tional 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 delinea- tion 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 carti- lage 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 abnor- malities; 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, malforma- tions 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 abnormal- ities are called epiphyseal, metaphyseal, or diaphyseal dysplasias, respec- tively. Some dysplasias are named for the segment of the limbs that shows the shortening, eg, rhizomelic (proximal), mesomelic (middle), and acro- melic (distal) dysplasias. Where the spine is involved, the prefix spondylo- is used, eg, spondyloepiphyseal dysplasias. Where the skull is involved, the prefix cranio- is used, eg, craniometaphyseal dysplasia. Other dys- Vol. 96, No. 3 SKELETAL DYSPLASIAS 815 September 1979 plasias are named for a combination of these features, eg, spondylome- taphyseal 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 (death- seeking) dysplasia, and metatropic (changing) dysplasia. There are a few conditions where a descriptive term is used based on concepts of patho- genesis, 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 osteo- chondrodysplasias 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 mani- festations throughout life. Careful physical examination may lead to diagnosis in some cases. The family history in every case is obligatory. Certain conditions may be
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