The genetics of diabetes.
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Diabetes Mellitus, Type 1↗
Biomedical subjects
D L Rimoin
Publications and source records attributed to D L Rimoin.
Dyssegmental dysplasias: clinical, radiographic, and morphologic evidence of heterogeneity.
The dyssegmental dysplasias are lethal forms of neonatal short-limbed dwarfism in which vertebral segmentation defects and short, thick, bowed long bones are the prominent radiographic features. Clinically, unusual facies, short neck, narrow thorax, cleft palate, and reduced joint mobility are commonly seen. To date, 18 cases of dyssegmental dysplasia have been reported. Reports of three pairs of affected sibs suggest autosomal recessive inheritance. We have studied eight additional cases of dyssegmental dysplasia, including one pair of affected sibs. Clinical, radiographic, and histologic examination of these new cases and review of the literature demonstrates the presence of at least two distinct forms of dyssegmental dysplasia. The milder form, "dyssegmental dysplasia, type Rolland-Desbuquois," is characterized clinically by frequent survival beyond the newborn period and by distinct radiographic changes resembling Kniest dysplasia. The severe form, "dyssegmental dysplasia, type Silverman-Handmarker," is characterized by stillbirth or death within the first few days of life and by distinct and more severe radiographic changes. In addition, we have demonstrated chondro-osseous morphologic differences between the two disorders by light and electron microscopy. We conclude that there are at least two forms of dyssegmental dysplasia, each autosomal recessive, which can be delineated on clinical, radiographic and morphologic grounds.
Abnormalities, Multiple↗
Prenatal diagnosis of osteogenesis imperfecta type III.
Ultrasonographic and radiographic evaluation of a fetus at risk for osteogenesis imperfecta (O.I) type III was performed. Real-time ultrasound measurements at 15 weeks gestation were interpreted as normal, but at 20 and 22 weeks of gestation revealed marked shortening of the long bones and deformity of the femurs. The findings were confirmed by fetal radiography at 22 weeks gestation. Radiographic and histologic changes characteristic of O.I. were observed in the aborted fetus. Thus the antenatal manifestations of O.I. type III maybe severe enough to make prenatal diagnosis possible in the second trimester for families at risk for recurrence of this disorder.
Adult↗
Fetal varicella syndrome.
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Abnormalities, Multiple↗
Osteogenesis imperfecta type III. Delineation of the phenotype with reference to genetic heterogeneity.
The existence of a rare form of osteogenesis imperfecta, OI type III, has been postulated. This is characterized by autosomal recessive inheritance with neonatal manifestations of bone fragility or deformability. It is usually nonlethal. Studies of some 345 pedigrees of OI in the last 8 years confirm that patients falling into this group are rare. They should be distinguished as a special group within the group of OI subjects with a progressively deforming OI phenotype delineated in previous publications [Sillence et al, 1979a, b]. The OI type III phenotype does not necessarily equate with progressively deforming OI, and probably only a proportion of cases with severe deformity and normal sclerae have OI type III. On the other hand, distinction between these patients and those with a milder form of perinatally lethal OI type II might be difficult. Whereas the natural history of skeletal deformity and fractures in patients with OI type III has certain similarities, variable severity between families indicates that OI type III is likely to be genetically heterogeneous.
Adolescent↗
Achondrogenesis II-hypochondrogenesis: variability versus heterogeneity.
Recently hypochondrogenesis was described as a form of neonatally lethal dwarfism said to resemble spondyloepiphyseal dysplasia congenita radiographically and achondrogenesis II morphologically. Because of the difficulty in distinguishing radiographically between mild achondrogenesis II and severe hypochondrogenesis, we performed a clinical, radiographic, and morphologic study of 24 cases originally classified as either achondrogenesis II or hypochondrogenesis, in an attempt to distinguish between heterogeneity and clinical variability. Review of the radiographic findings in these cases show a fairly continuous spectrum of bony defects, rather than two distinct radiographic syndromes. Chondro-osseous histology and ultrastructure was similar in all cases regardless of severity and was characterized by hypervascularity and hypercellularity of the cartilage with multiple small, round dilated cysternae of rough endoplasmic reticulum. These findings suggest that hypochondrogenesis and achondrogenesis type II represent a spectrum with marked phenotypic variability.
Bone and Bones↗
Chromosomal mosaicism in the Killian/Teschler-Nicola syndrome.
We report a patient with the Killian/Teschler-Nicola/Pallister mosaic syndrome in association with a cytogenetic abnormality. This patient is the first reported to have lymphocyte mosaicism for an isochromosome of 12p. All other patients with the Killian syndrome have had normal lymphocyte karyotypes, although mosaicism for a similar isochromosome of 12p has been reported in the fibroblasts of most patients with the Killian syndrome.
Abnormalities, Multiple↗
A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia.
We describe the clinical, radiographic, histopathologic, and ultrastructural features of a distinct neonatal lethal chondrodysplasia inherited as an autosomal recessive trait. The characteristic radiographic findings consist of flattened, hypoplastic vertebral bodies; short ribs; hypoplastic iliac bones with "a snail-like" configuration; short, broad long-bones with dumbbell-like appearance; short and wide fibula; and precocious ossification of the tarsus. Chondro-osseous histology is characteristic with hypervascularity, increased cellular density, and normal size chondrocytes with a centrally located round nucleus and absence of lacunar space. Because of the snail-like radiographic appearance of the pelvis in this disorder, we propose the name "Schneckenbecken dysplasia" (ie, German for snail pelvis).
Dwarfism↗
Pseudodiastrophic dysplasia: a distinct newborn skeletal dysplasia.
Pseudodiastrophic dysplasia is a distinct disorder that differs from diastrophic dysplasia on the basis of clinical, radiographic, and chondro-osseous histopathologic findings. In addition to the rhizomelic shortening of the limbs and severe clubfoot deformity, which suggest the diagnosis of diastrophic dysplasia, distinguishing features are elbow and proximal interphalangeal joint dislocations, platyspondyly, and scoliosis, which are observed in infancy. This disorder has been reported previously in three infants, all of whom died in the first year of life. Two of these were sisters, suggesting autosomal recessive inheritance. We report four new patients with this distinct skeletal dysplasia, including two children now older than 4 years of age. In both of these patients neonatal contractures have improved with physical therapy and scoliosis has progressed significantly.
Bone Diseases, Developmental↗
A new skeletal dysplasia: clinical, radiologic, and pathologic findings.
Two siblings, one male and one female, were noted to have a distinct skeletal dysplasia. The clinical and radiographic features resemble those observed in Kniest dysplasia and Rolland-Desbuquois syndrome, but important differences were noted. Specifically, these two patients have microstomia, "pursed" lips, and ectopia lentis, and their radiographs reveal no coronal clefts. Chondro-osseous features also differ from those observed in either of the other disorders. Scattered dense patches consisting of collagen fibers 10 to 30 times broader than normal are seen scattered throughout the cartilage matrix; the "Swiss cheese" appearance characteristic of Kniest dysplasia is not observed. These patients appear to have a new skeletal dysplasia, most likely inherited in an autosomal recessive fashion.
Bone Diseases, Developmental↗
New frontiers in genetic medicine.
Disorders determined wholly or in part by genetic factors constitute a substantial number of human diseases. This realization has grown during the past 2 decades with the recognition of many specific heritable conditions and the identification of familial risk factors for common disorders. New technologies, such as fetal visualization, chorionic villus sampling, molecular cloning methods, and gene transfer technology, provides a framework for dealing with genetically determined illness in unprecedented ways. Several current and potential applications of these methods are examined, as is the use of restriction fragment length polymorphisms to survey the variability within the genome and to generate markers permitting the prospective detection of genetic disorders. The promise and limitations of chorionic villus biopsy sampling are considered for early prenatal diagnosis. The future of gene therapy in hereditary diseases is examined, and some of the substantial social and ethical considerations engendered by these new developments are explored.
Abortion, Spontaneous↗
Short stature--physiology and pathology.
Stature, the quantitative measure of height, varies widely within each ethnic group with a fairly normal distribution. Of the numerous patients whom physicians encounter because of short stature, relatively few are pathologically small in the context of family and ethnic background. Physicians must be able to differentiate pathologic short stature from the lower end of the normal curve before embarking on a complex diagnostic evaluation. There are literally hundreds of different causes of short stature, and the clinical evaluation requires a wide variety of clinical, radiographic, pathologic and biochemical tools. Although specific treatment to promote growth is available only in persons with the endocrinopathies and the acquired nutritional, emotional and chronic disease states, diagnosis of the specific form of short stature can have great importance in being able to prevent complications and to offer accurate prognostic information and genetic counseling.
Body Height↗
Histopathologic examination in osteochondrodysplasia. Time for standardization.
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Decalcification Technique↗
Oto-palato-digital syndrome, type II--an X-linked skeletal dysplasia.
We report on two male infants with a lethal skeletal dysplasia characterized by cleft palate, midface hypoplasia, downward-slanting palpebral fissures, small thorax, and bowed limbs with absent fibulae. The clinical and radiographic changes are similar to those seen in the recently proposed oto-palato-digital syndrome, type II [Fitch et al, 1983]. The disorder is X-linked with heterozygous females being more mildly affected.
Bone Diseases, Developmental↗
Computerized tomography of the foramen magnum: achondroplastic values compared to normal standards.
Computerized tomographic dimensions of the foramen magnum of 63 achondroplastic individuals were compared to standards established for nonachondroplastic individuals. The size of the foramen magnum in patients with achondroplasia was small at all ages, particularly in those with serious neurologic problems. The data suggest that measurement of the foramen magnum may identify achondroplastic individuals at high risk of developing neurologic complications.
Achondroplasia↗
Chondrodysplasia punctata in an infant with duplication 16p due to a 7;16 translocation.
This paper describes a newborn with a number of clinical manifestations compatible with duplication 16p due to a 46, XY, -7, +der (7), t(7;16) (p22;p13) pat karyotype. In addition, the baby had chondrodysplasia punctata, whose distribution of lesions did not match any of the well-documented forms of these disorders. The baby also had microcornea and lacked a gallbladder, two features, in addition to chondrodysplasia punctata, that have not previously been noted in cases of duplication 16p.
Chondrodysplasia Punctata↗
The role of mesenchyme-like tissue in the pathogenesis of thanatophoric dysplasia.
We have studied the light microscopic, transmission, and scanning electron microscopic (SEM) findings in 13 cases of thanathophoric dysplasia (TD) and 4 control infants. In the TD growth plate, areas with less abnormal cartilage and bone alternated with areas of severely abnormal cartilage and bone. These latter abnormal areas were always found around tongues of apparent mesenchymal tissue that appeared to penetrate from the investing perichondrium and periosteum. The ultrastructure of the less abnormal areas was similar to that of the control infants, including cell and matrix structure as well as mineralization. The abnormal cartilage and bone had many ultrastructural abnormalities that were also found in the adjacent mesenchymal tissue. The mesenchymal cells, adjacent chondrocytes, and osteoblasts contained dilated endoplasmic reticulum and moderately large intracytoplasmic vacuoles. In the area adjacent to the cartilage, the matrix of the apparent mesenchyme contained thin collagen fibers and proteoglycan granules, whereas the matrix adjacent to the bone contained thick bundles of short collagen fibers. The matrix of the surrounding cartilage and bone resembled the adjacent matrix in the mesenchyme. In addition, many vesicular structures or osmiophilic particles were found in the matrix of the mesenchyme and adjacent cartilage and bone. SEM examination showed normal and abnormal bone trabeculae adjacent to each other. In the abnormal trabeculae, there were large, densely packed osteoblastic and osteocytic lacunae. The calcified collagen fibers had a random orientation, in contrast to the longitudinal orientation in the relatively normal bone. Chemical studies of collagen in the metaphyses of bones from five infants with TD showed a small amount of collagen type III (less than 5%), which was not found in three control infants. Thus, a basic pathogenetic mechanism in the skeletal abnormalities of TD appears to be the focal replacement of the growth plate and periosteum by persisting abnormal mesenchymal-like tissue from which the abnormal bone originates.
Bone Development↗
Histologic and ultrastructural studies on the mineralization process in hypophosphatasia.
Chondroosseous tissue from six infants with infantile hypophosphatasia and six control infants were studied by light, transmission, and scanning electron microscopy. Alkaline phosphatase histochemical reaction of the growth plate was studied in two infants and was greatly reduced when compared to two control infants. Hypertrophic chondrocytes were increased in number with persisting cartilage islets in the metaphysis. In five of the six cases studied, chondrocytes and intercartilagenous intercellular chondroid matrix appeared ultrastructurally normal. Matrix vesicle distribution was similar to that of control subjects, but they were associated with few mineral crystals. In two infants, the matrix vesicles were alkaline phosphatase nonreactive. In the calcifying zone of the growth plate and in the newly formed metaphyseal trabecular bone, cartilagenous calcospherites often were small and the orientation of crystals was nonradial when compared to that of control infants. The mineralization of diaphyseal bone appeared normal. It seems that matrix vesicles are present in hypophosphatasia and that the impaired mineralization of cartilage is due primarily to the deficiency of alkaline phosphatase. In spite of the lack of alkaline phosphatase, secondary mineralization of bone which is not mediated by matrix vesicles was normal.
Alkaline Phosphatase↗