David W. Hollister

Collagen heterogeneity in human cartilage: Identification of several new collagen chains

Normal human hyaline cartilages contain five distinguishable coltagenous proteins in addition to, and different from the αl(II) chain of Type II collagen. This report describes the characterization of three of these additional proteins. By the criteria of solubility, electrophoretic mobilities, ion-exchange and sieve chromatographic properties, amino acid compositions, and cyanogen bromide peptide profiles, at least two of these proteins, and possibly the third, are structurally distinct collagen α chains different from previously reported collagen chains. These findings imply further molecular heterogeneity of vertebrate collagens, and the existence of at least 9 different structural genes for collagen chains.

Heritable Disorders of Connective Tissue: Ehlers-Danlos Syndrome

The Ehlers-Danlos syndrome is a relatively common heritable disorder of connective tissue. The cardinal features are cutaneous hyperextensibility, joint hypermobility, bleeding diathesis, and tissue fragility, and these features lead to a large variety of additional manifestations. Of the eight presently described types, four varieties have been found to be caused by defects in the biogenesis of collagen, the major structural protein of the body. Consideration of the clinical features and probable mode of inheritance will permit subclassification of many patients into specific types, and biochemical confirmation is possible for several varieties.

The lacrimo-auriculo-dento-digital syndrome

A syndrome characterized by obstruction of the nasolacrimal ducts, hypoplasia or aplasia of the lacrimal puncta, cup-shaped ears, hearing loss, dental and digital malformations is described. A Mexican father and five of his eight children are affected, suggesting an autosomal dominant mode of inheritance. The name “lacrima-auriculo-dento-digital syndrome” is proposed for this disorder.

Further heterogeneity within lethal neonatal short-limbed dwarfism: The platyspondylic types

Twelve infants, initially considered to have thanatophoric dysplasia, were studied by a combined radiographic-histochemical-biochemical approach. Three distinct forms of platyspondylic lethal neonatal short-limbed dwarfism could be distinguished: (1) Thanatophoric type, (2) Torrance type, and (3) San Diego type. The latter two disorders had similar radiographic abnormalities that were clearly different from those of typical thanatophoric dysplasia. All three disorders had clearly different condroosseous histopathologic abnormalities. Preliminary biochemical studies have revealed different electrophorectic abnormalities in solubilized type II collagen chains of cartilage in each of these three disorders.

Genetic Disorders of Collagen Metabolism

The first of the true genetic disorders of collagen metabolism, lysyl hydroxylase deficiency, was described in 1972 (Pinnell et al., 1972), and since that time there has been continued expansion of the biochemical understanding of inherited connective tissue disorders that involve collagen. In that period abnormalities in collagen structure, biosynthesis, post-translational modification, and degradation have been identified in the Ehlers-Danlos syndrome, the Marfan syndrome, osteogenesis imperfecta, cutis laxa, a small number of chondrodystrophies, and forms of epidermolysis bullosa.

The Winchester syndrome: a nonlysosomal connective tissue disease.

The Winchester syndrome, a recently recognized inherited disorder of connective tissue, consists of dwarfism, contractures, skin lesions, corneal opacities, osteoporosis, carpal-tarsal osteolysis, and rheumatoid-like small joint destruction. We have studied the third, fourth, and fifth recognized cases of this disorder and find: (1) progressive lysis of carpal and tarsal bones; (2) replacement of bone and cartilage by dense fibrous tissue containing abnormal blood vessels; (3) scanty trabecular and cortical bone, but normal resting cartilage and growth plates; (4) hypervascularity apparently associated with osteolysis at large joints; and (5) widespread proliferation of ultrastrurally abnormal fibroblasts. Although this disorder was originally postulated to be a new mucopolysaccharidosis, we find no evidence for a lysosomal storage disease, and propose reclassification of this disorder as a nonlysosomal connective tissue disease.

Chondro-osseous pathology in the chondrodystrophies.

The majority of chondrodystrophies are associated with distinct abnormalities in chondro-osseous histopathology. In some disorders, the pathological abnormalities are characteristic and can be used as diagnostic criteria, in other instances the morphological abnormalities are not specific, and in still others, no abnormality in chondro-osseous morphology is present. In this paper, the chondro-osseous histopathology and ultrastructure of a number of chondrodystrophies are reviewed to illustrate the different pathogenetic mechanisms involved in each of these disorders.

An in vitro model for the study of enzymatically mediated biomechanical changes in the chorioamniotic membranes.

The effects of different incubation media on the biomechanical properties of nine chorioamniotic membranes were studied. Significant alterations in strain/rupture, work/rupture, and rupture/tension values have been demonstrated after a 24 hour incubation period in pseudoamniotic fluid (PAF). These changes can be arrested if enzyme inhibitors are added to the incubation media. This study suggests that biomechanical alterations in the chorioamniotic membranes may be biomechanical, namely, enzymatically mediated.

Familial laryngomalacia: A case report†‡

This report describes the hereditary occurrence of severe laryngomalacia in three of five siblings of a Mexican‐American family. The mother, who experienced respiratory difficulties in the first year of life, may also have been affected. All three affected children required neonatal tracheostomy, and two died of pulmonary complications. Histological studies of tracheal cartilage revealed distinct hypercellularity and histochemical staining abnormalities of the cartilaginous matrix without defects in skeletal cartilage.

Diastropic Dwarfism: a Histochemical and Ultrastructural Study of the Endochondral Growth Plate

Summary: Chondro-osseous tissue from five patients with diastropic dwarfism was studied by histologie, histochcmical, and electron microscopic methods. The major abnormalities observed were: 1) irregular distribution of chondrocytes undergoing degeneration in the resting cartilage; 2) abnormal distribution of collagen in the resting cartilage; 3) a spectrum of fibrous matrix lesions in the resting cartilage which ranged from focal areas of aggregated collagen fibrils to large cystic lesions in which intracartilagenous ossification occurred; and 4) shortened, irregular cellular columns within the growth plate which were occasionally disrupted by matrix lesions extending from the resting cartilage. These alterations in chondro-osseous morphology have not been observed in any of the other skeletal dysplasias examined to date and appear to be pathognomonic for this disorder.Speculation: The basic abnormality in diastropic dwarfism may be a metabolic abnormality in the chondrocyte which predisposes it to cell death or a processing defect in its synthesis of either collagen or proteoglycan. An enzyme deficiency could produce either type of defect and would be consistent with the autosomal recessive inheritance of this disorder.