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Medical genetics emerged from a basic science only one half century ago. Scientists and physicians housed in a variety of basic science and clinical departments have accomplished many of the major advances in the study of genetic diseases in children. A scientific approach to human genetics emerged in 1948 with the establishment of the American Society of Human Genetics. Even before the use of modern laboratory techniques, Pediatric departments spearheaded the clinical description of simple genetic disorders, syndromes, and major malformations. The burgeoning of medical genetics as a specialty and its tremendous growth in departments of pediatrics was stimulated by major technological advances, such as the ability to visualize human chromosomes, the development of methods to study biochemical variations in blood and urine, cell culture, somatic cell hybridization, and molecular technology, all of which allowed for the diagnosis, treatment, and prevention of genetic disorders in children. Many pediatricians sought training in genetics, and training programs in medical genetics flourished in departments of pediatrics. The explosion of knowledge concerning the metabolic and molecular causes of genetic disease and understanding of their pathogenesis has led to a variety of specific diagnostic, preventive, and therapeutic approaches for alleviating the symptoms or preventing the complications of many of these disorders. Medical genetics is now recognized as a distinct medical specialty with its own American Board of Medical Specialties approved board (American Board of Medical Genetics) and clinical specialty college (American College of Medical Genetics).

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.

The mean number of cells per cartilage column and the proportion of hypertrophic and proliferative chondrocytes per column were determined in the costochondral junction in a population of normal subjects including 10 fetal-newborns and 15 subjects aged 0.3-16 y of age. Both the mean number of cells per column and the proportion of proliferative cells per column were significantly greater in the fetal-newborn population compared to the pediatric population (12.6 +/- 1.0 versus 8.4 +/- 0.4, p less than 0.001 and 39.6 +/- 6.9 versus 24.4 +/- 2.5, p = 0.025, respectively) (mean +/- sem [n]). The number of cells per column bore a significant negative relationship to subject age (r = -0.52, p = 0.007). Significant positive correlations were found between the mean number of cells per column and age-specific growth velocity both in males (length-height velocity = [(6.3) (mean number of cells) - 44.1], r = 0.72, p = 0.02) and in females (length-height velocity = [(3.4 (mean number of cells) - 14.4], r = 0.77, p = 0.006). These data will provide normative values against which abnormalities characteristic of the skeletal dysplasias can be compared.

Summary: Chondro-osseous tissue from four patients with the Kniest dysplasia was studied histochemically using a new plastic embding technique. Extensive vacuolar changes were observed p-1 throughout the endochondral growth plate and adjacent resting cartilage. These changes occurred within the cartilage matrix and also in the lacunae of degenerating chrondrocytes. The septa of the lesions contained chondroitin sulfate, but little keratan sulfate or collagen. Resting cartilage not adjacent to the growth plate stained irregularly and showed few of the vacuolar lesions, and chondrocytes were enlarged and contained cytoplasic inclusions, but no vacuolar material. Thus, there appears to be a sequence of events initiated by cellular accumulation of a substance and progressing to cellular and matrix degeneration. Speculation: The findings suggest that there may be a defect in the synthesis, structure, or secretion of a major cartilage matrix component (e.g, proteoglycan, collagen) which leads to its accumulation in the chondrocyte rough endoplasmic reticulum. Both cellular and matrix degeneration subsequently occur either due to a toxic effect of this material or to the absence of the normal molecule.

In recent years the extent of the heterogeneity within lethal neonatal short limbed dwarfism has become apparent, with the delineation of numerous distinct syndromes such as thanatophoric dwarfism, achondrogenesis and the short rib polydactyly syndromes. Utilizing a combined clinical, radiologic, histologic and biochemical approach, we have observed further heterogeneity within this group of disorders. For example, we feel we can distinguish at least 3 distinct disorders in what has been called “thanatophoric” dwarfism, by histological and biochemical criteria. One group of patients is recognized by the Kleeblattschadel skull deformity. They differ both radiologically and in the histologic appearance of their growth plates from patients not manifesting this deformity. In this latter group, 2 additional disorders can be distinguished by specific growth plate histopathology and biochemical abnormalities observed on whole chain electrophoresis of collagen isolated from resting cartilage. Similarly, 2 distinct varieties of achondrogenesis can be clearly separated by radiologic and histopathologic criteria. The short rib polydactyly syndromes were originally divided into the Majewski and Saldino-Noonan types on the basis of radiologic criteria. He feel that the latter type can be further subdivided into 2 distinct entities. These studies demonstrate that the true heterogeneity of this group of disorders is only beginning to be appreciated, and that further heterogeneity will likely be found by this multidisciplinary approach.

McKusick first described cartilage-hair hypoplasia (CHH) as a common type of dwarfism in the Old Order Amish. We have found a high frequency of CHH (at least 30 patients in a population of 4.6 million) in Finland. In order to characterize the clinical variability of this disorder, 13 males and 15 females from 1 to 23 years of age were studied (anthropometric measurements, skeletal x-rays, gastrointestinal malabsorption tests and a variety of immunologic tests). The measurements demonstrated the severe disproportion of the dwarfism, but also revealed the presence of vertebral involvement which had been previously overlooked. Even within this homogeneous group of patients, marked variability in the degree of dwarfism, body disproportion and hair diameter was found. Two cases of mild malabsorption were found in addition to one male who had been operated upon for congenital megacolon. Earlier studies have indicated severe and even fatal immunodeficiency against viral infections in CHH. All immunological studies in these patients were normal except for constantly low lymphocyte PHA stimulation indicating a defect in cell-mediated immunity. Tuberculin skin tests were negative in 61% of the patients in spite of prior BCG. This study demonstrates the high frequency of CHH in Finland and the marked variability in the expression of this autosomal recessive disorder.

The Kniest syndrome is an autosomal dominant skeletal dysplasia characterized by dwarfism, dysmorphic facies, short extremities and joint swelling. Increased urinary excretion of keratan sulfate (KS) in this syndrome has recently been discovered. To identify further the KS in the Kniest syndrome, analysis of the purified KS was carried out using gas liquid chromato-graphy (GLC). Mucopolysaccharides from urine of 4 patients with Kniest syndrome were isolated and KS was purified using Dowex-1 ion exchange chromatography. Keratan sulfate fractions were meth-anolyzed at 80° for 18 h. Amino sugars were N-acetylated with trifluoroacetic anhydride, and following silylation the material was analyzed by GLC. The Kniest KS was compared to Morquio KS and also to standard KS isolated from corneas and rib cartilage. The results indicate that the KS from Kniest and Morquio syndrome are identical. Equimolar amounts of galactose and N-acetyl-glucosamine were found, fucose, mannose, N-acetylgalactosamine and sialic acid, which are found in KS, were also present. The chromatograms of standard skeletal KS correspond to KS from these 2 syndromes. Urinary mucopolysaccharides from normal individuals show different chromatograms as do mucopolysaccharides from urine of a patient with Sanfilippo syndrome. These results indicate that GLC can be used to characterize KS in urine of patients with the Kniest syndrome. GLC may be useful for screening of skeletal dysplasias for keratan sulfaturia.