Ossification Defects Research Articles

Tissue disposition of carbon disulfide. II. Whole-body autoradiography of 35S- and 14C-labelled carbon disulfide in pregnant mice.

Occupational exposure to carbon disulfide (CS2) has been associated with an increased rate of spontaneous abortions. Animal experiments have shown that CS2 is embryotoxic and teratogenic. In the present study, the embryonal and foetal distribution of CS2 and its metabolites was studied after administration of 35S- or 14C-labelled CS2 to pregnant mice in different stages of gestation. CS2 and its metabolites passed the placenta at all stages of gestation. High levels of metabolites of CS2 were registered in the embryonic neuroepithelium. In mid and late gestation CS2 itself accumulated in the cerebrospinal fluid (CSF) of the brain. 14C-labelled metabolites of CS2 showed affinity for bone and were retained in the liver even at long survival times (24 hours). These localizations may be of significance for some of the reported teratogenic effects of CS2, such as hydrocephalus, ossification defects and foetal liver injury, and support the idea that CS2 and/or its metabolites are embryotoxic and teratogenic by acting directly on embryonal and foetal structures.

Osteogenesis imperfecta type II delineation of the phenotype with reference to genetic heterogeneity.

A group of fetuses with a perinatally lethal variety of osteogenesis imperfecta (O.I. type II) is characterized by short limbs, and clinical and roentgenological evidence of severe osseous fragility and defective ossification. Forty-eight cases were reviewed and can be subdivided into 3 groups on the basis of small but probably significant differences in clinical and radiographic findings. Group A (38 cases): short, broad, "crumpled" long bones, angulation of tibiae and continuously beaded ribs. Group B (6 cases): short, broad, crumpled femora, angulation of tibiae but normal ribs or ribs with incomplete beading. Group C (4 cases): long, thin, inadequately modelled, rectangular long bones with multiple fractures and thin beaded ribs. Consistency of findings within sibships suggests the groups reflect genetic heterogeneity. An increased frequency of parental consanguinity, sib occurrence with normal parents, and normal mean paternal age at birth, suggest that most cases of O.I. type II represent autosomal recessive traits. Some previously reported cases and the biochemical findings in one case suggest still further genetic heterogeneity.

Bilateral choanal atresia in two members of one family

Two children are presented with bilateral choanal atresia: a girl with the typical features of the Treacher Collins syndrome, and a boy, a third cousin of the girl, without mandibulo-facial dysostosis. Simultaneous occurrence of choanal atresia and the Treacher Collins syndrome may be based on a defective ossification of the mesenchyme of the first visceral arch. Choanal atresia may be due to nonabsorption of the bucconasal membrane and/or extension of the sphenoid or palate bone.

Teratogenicity in the rat of the venom from the scorpion Androctonus amoreuxi (Aud. & Sav.)

A. amoreuxi venom caused a high foetal resorption rate in rats, particularly when injected on days 9–11 of gestation. Vertebral and ossification defects and foetal weight loss were observed in many of the viable foetuses obtained from mothers treated with scorpion venom. Treatment of the rats with phentolamine in addition to the venom significantly reduced the venom-induced hyperglycemia. It also conferred some protection against foetal resorption but had only a slight effect on chondrification or foetal weight loss. This shows that hyperglycemia might be responsible for foetal mortality, but alone is not a decisive factor in the effect of the venom on the chondrification process. Treatment of the rats with triamterene reduced the foetal resorption rate and significantly decreased the effects of the venom on chondrification. However, marked stippling was observed in the long bones and was ascribed to marked mobilization of ionized calcium in the foetus. Foetuses removed from rats treated with phentolamine or triamterene in addition to the venom, however, showed flattened and depressed skulls, possibly from a missing 1st cervical vertebra or failure of the occiptal fontanel to close. Treatment of the rats with the scorpion venom over a longer period of time and starting at an earlier time of gestation (days 7–14) caused total foetal resorption, which may be due to inhibition of histamine formation by the venom. The teratogenic effect of the venom appears to be the result of its metabolic effect and action on body electrolytes of the maternal animal, rather than to a direct effect on the foetuses. This was evidenced from experiments with labelled venom, where only a small fraction (0.08-0.33%) was detected in foetuses or placenta.

Dyggve-Melchior-Clausen syndrome. A histochemical study of the growth plate.

The Dyggve-Melchior-Clausen syndrome is a rare inherited disorder in which a major feature, the skeletal dysplasia, is thought to result from a defect in endochondral ossification. To further characterize this disturbance, histochemical studies were performed on an iliac-crest biopsy specimen from a patient with disorder. The use of plastic embedding methods permitted previous observations, which were based on decalcified paraffin-embedded tissues, to be extended and a variety of new ones to be made. The resting cartilage matrix was very fibrous. In many areas it consisted of randomly oriented bundles of loosely woven fibers that stained as collagen. The chondrocytes in this region were excessively vacuolated and many contained cytoplasmic inclusions that stained non-specifically as protein. Cartilage canals were prominent in the resting cartilage. In many areas, clusters of degenerating chondrocytes and occasional vacuolar lesions replaced the columns of proliferating and maturing cells that normally occupy the growth-plate region. There was coarse and irregular calcification of these clusters at the chondro-osseous junction, and intracartilaginous ossification was also found. These observations further define the histological criteria for the diagnosis of this disorder and provide new insights into its pathogenesis.

Meticulous control of diabetes during organogenesis prevents congenital lumbosacral defects in rats.

Lumbosacral defects occur in the offspring of the diabetic rat in a fashion analogous to those occurring in infants of diabetic human mothers. To test the hypothesis that control of diabetes during the critical period of organogenesis can affect the incidence of these defects, diabetes was produced by streptozotocin in pregnant rats on day 6 of gestation. One group of pregnant rats was treated with saline (group 2), while another (group 4) received insulin twice daily between days 6 and 13. The incidence of lumbosacral malformations in the fetuses was then compared between these groups, with a pregnant, nondiabetic control group (group 1), and with a group of rats in whom diabetes was produced by streptozotocin on day 12, after the critical period of fusion of the lumbosacral spine (group 3). Two types of lumbar and/or sacral malformations were noted: a fusion defect and an ossification defect. In the nondiabetic animals (group 1), only 1 out of 59 fetuses had an abnormality. Diabetes produced after the period of fusion of the neural tube in the lumbosacral area (group 3) had no effect on the incidence of lumbosacral malformations (0 out of 54). Diabetes treated with saline during the period of organogenesis (group 2) was associated with lumbosacral malformations in 25 of 146 fetuses, which was significantly increased (P < 0.005) when compared with the nondiabetic pregnant animals. Insulin treatment during the period of organogenesis (group 4) significantly reduced (P < 0.005) the number of lumbosacral defects (5 of 106) from that observed in the diabetic animals treated with saline. When the results of the insulintreated diabetic group were further analyzed, the incidence of malformations (5 of 58) in the animals that exhibited intermediate hyperglycemia during the period of organ differentiation [two or more serum glucose values greater than 200 mg/dl, (group 4A)] was not significantly different from that observed in the saline-treated diabetic group (P > 0.1). This occurred despite a mean glucose concentration during the period of insulin treatment that was significantly lower than the saline-treated diabetic controls (180 ± 16 mg/dl vs. 348 ± 16, P < 0.001). In contrast, the incidence of lumbosacral malformations (0 of 48) observed in the fetuses of those diabetic animals in whom insulin therapy produced normal serum glucose concentrations (122 ± 9 mg/dl) during the period of organogenesis (group 4B) was sharply reduced from that seen in the fetuses taken from the saline-treated diabetic mothers who had not received insulin (P < 0.001). These data are consistent with the thesis that (1) uncontrolled diabetes produces lumbosacral malformations only during the period of organ differentiation, (2) control of diabetes during the period of organ differentiation reduces the incidence of malformations, and (3) the “quality” of that control is quite important, because normal to near-normal serum glucose concentrations must be achieved in order to be effective.

Teratogenicity of diphenylhydantoin in the New Zealand white rabbit

AbstractThe teratogenic potential of diphenylhydantoin sodium (DPH) was investigated in the rabbit after oral intubation of 0 (Control), 25, 50, 75, 100, and 150 mg/kg/day from days 7–18 of gestation. Except for reduced maternal weight gains at the two higher dosages, no other obvious pharmacological or toxic effects were noted in treated rabbits.Dose‐response‐related increases in the resorption and malformation rates were observed. Four litters (one of 14 litters with viable fetuses at 75 mg/kg/day and three of eight litters with viable fetuses at 100 mg/kg/day) exhibited a similar pattern of multiple malformations that included some or all of the following defects: open eyes, cleft palate, and limb abnormalities that included shortened and curved long bones, pes caves, syndactyly, and ossification defects of the phalanges. Dosages of 150 mg/kg/day produced nearly complete resorption, which may have masked the teratogenic response to the drug.

Non-Majewski short rib-polydactyly syndrome.

Clinical, radiographic, and morphologic studies of non-Majewski short rib-polydactyly cases show a spectrum of abnormalities. While the findings of Yang et al reported in this journal suggest that a unique change in chondrocytes, namely PAS-positive inclusions, might distinguish one group of patients from another, experience with 4 other cases with radiographic findings similar to the case reported by Yang and colleagues does not confirm the finding. Therefore, the full significance of their observation must await further morphologic studies of these patients. The clinical findings are extremely variable, and no feature is pathognomonic of either of the groups of patients. Similarly, the radiographic findings show a spectrum of severity. The original cases of Saldino and Noonan have a more severe ossification defect in the long bones and pelvis than any of these other cases. While genetic heterogeneity might be invoked to explain this wide spectrum of findings in these patients, at present, variability in expression in just as likely a hypothesis.

Cleidocranial dysplasia. A family study

The incidental observation of Wormian bones in the skull and defective ossification of the public symphysis in a mildly scoliotic 12-year-old girl prompted a clinical and radiological study of members of her family. The diagnosis of cleidocranial dysplasia (CCD) was established by observing similar skeletal abnormalities in eight out of ten of them but the classical clavicular defect in only one, the last to be examined. Abnormal modelling of the medial end of both clavicles was observed in all those affected. A modelling defect of the public bones is suggested as an additional, hitherto undescribed, radiological sign. The progression with age of certain radiological features of CCD is discussed. It is suggested that this family represents an atypical variant of CCD. Such variance may be more prevalent in patients with mild scoliosis than presently suspected. A complete skeletal survey with espeical attention to the skull, pelvis and medial aspect of the clavicle and family studies may be essential for the definitive diagnosis of CCD in certain patients.

The Histological Characteristics of Congenital Coxa Vara

In a 51/2 year old boy with unilateral coxa vara who died of unrelated causes histological sections were made of the proximal femora and pelvic growth plates. The proximal femora were also perfused to study the pattern of arterial supply. Evidence of active endochondral ossification was not detectable in growth plates of the affected right femur, the clinically and roentgenographically normal left femur and the pelvis, including a Salter Type II fissure fracture. The endochondral ossification defect found in growth plates of the proximal right femur and pelvis was associated with a reduction in the number and caliber of intraosseous arteries supplying the metaphyseal sides of the growth plates in the proximal femur and those supplying the subchondral region and extraosseous medial ascending cervical arteries on the surface of the femoral neck. This deficiency in endochondral ossification resembles a form of dwarfism associated with a coxa vara and a generalized growth plate disorder.

Tolbutamide and Achondroplasia

To the Editor.— In MEDICAL NEWS (226:617, 1973), Tolbutamide Aids Youth With Achondroplasia reports opinions from an interview with Platon J. Collip, MD. The conclusion drawn by Dr. Collip that achondroplasia is not a primary disorder of bone and cartilage, but a generalized disorder based on glucose intolerance is without fact. There has been no corroboration of glucose intolerance in achondroplasia. In a large number of achondroplastic patients seen by us, glucose tolerance tests have been perfectly normal. In addition, achondroplasia is a dominantly inherited disorder, which strongly argues against an inborn error of metabolism being the primary defect. Rimoin et al have adequately demonstrated that achondroplasia is a quantitative defect in endochondral ossification. Collip did metabolic studies in 1972 on animals thought to be achondroplastic, but these animals, which previously were considered to yield examples of achondroplasia on the basis of histological studies, clearly exhibited a different disorder, not

Absence of erythrocyte adenosine deaminase associated with severe combined immunodeficiency

Hereditary absence of adenosine deaminase activity in erythrocytes was found in an infant with severe combined immunodeficiency. Immunoglobulins were markedly decreased. Lymphocytes failed to transform with either phytohemagglutinin or concanavalin. At autopsy the thymus was rudimentary and there was a striking absence of lymphoid elements throughout the lymphoreticular system. The costochondral junction of the ribs showed widening and cupping of the metaphyseal plates, and the metaphysis of the long bones demonstrated lucent bands suggestive of a defect in ossification. The association of combined immunodeficiency with the genetically determined absence of erythrocyte-type adenosine deaminase appears now to be a specific clinical entity.

A morphological and histochemical study of thalidomide-induced upper limb malformations in rabbit fetuses.

AbstractThe upper limbs of 21‐day‐old thalidomide‐treated rabbit fetuses were studied macroscopically, histologically, and histochemically. The deformed limbs were arthrogrypotic, twisted, or medially rotated and inverted. Often these malformations were coupled with anomalies of the thumb. One or more of the preaxial bones or their primordia were either anomalous or missing. The degree of the induced dysmelia could be recognized by the graded severity of the histology. The least severely affected limbs exhibited defects of ossification and/or chondrification, whereas more severely affected ones contained atrophic chondrocytes, undifferentiated mesenchyme, or absence of primordia. In the deformed limbs glycogen was retained in the hypertrophic and calcified chondrocytes and glycogen granules were dispersed in reduced thenar structures, but alkaline phosphatase activity was reduced or absent in the same areas. There were no detectable differences in the amount or distribution of acid mucopolysaccharides between abnormal and control limbs. However calcium deposition in the cartilaginous matrices was reduced or absent in the abnormal limbs. In limbs with reduced amounts of osseous tissue there was no evidence of histochemical aberration in the deposited bone. It would appear, therefore, that thalidomide affected mesenchymal derivatives at various stages of development; that it was associated directly or indirectly with the utilization of glycogen and the production of alkaline phosphatase; and that its influence was expressed by aberrations in the chondrification and calcification processes during later fetal development.

Metaphyseal chondrodysplasia calcificans. A report on two cases

Two cases of a new bone disease characterized clinically by progressive deformity and radiographically by metaphyseal dysplasia with massive deposits of calcified densities and extensive defects of ossification, with proliferation of cartilage, are described. The growing parts of epiphyses are also affected. An increased excretion of mucopolysaccharides and hyperactivity of at least one lysosomal enzyme in the leucocytes were found in the patient observed in the Netherlands. In differential diagnosis, the metaphyseal chondrodysplasia of Jansen and enchondromatosis, with the Mafucci syndrome variant should be considered. We are extremely grateful to Dr. Maroteaux, of Paris, for arranging contact between the authors of this article.

Cleidocranial dysostosis: psychological observation of two cases.

The syndrome of cleidocranial dysostosis was first reported by Marie and Sainton in 1898. It is a congenital condition giving rise to a defect in ossification. The principal clinical features are dwarfism, a large head with a small fades, and a depressed or saddle-shaped nose. The clavicles are incomplete or absent, scapulae are small and poorly formed, and frequently the symphysis pubis fails to fuse.

Roentgenology of the median cleft face syndrome.

In our continuing study of median craniofacial anomalies, we have found it convenient to subdivide cases on the basis of the interorbital distance. Orbital hypotelorism in combination with a proboscis or with a flat nose and median cleft lip reliably predict a brain that has failed to divide into cerebral hemispheres (holoprosencephaly) (3). The close correlation between face and brain in these patients prompted us to study the median facial anomalies associated with orbital hypertelorism (1). This communication reiterates the results of that study with emphasis on the roentgen characteristics. Classification and Roentgen Description Orbital hypertelorism occurs repeatedly with six other median facial anomalies: (a) low “V”-shaped frontal hairline, (b) cranium bifidum occultum frontalis, (c) primary telecanthus (lateral displacement of the medial canthi relative to the pupils), (d) median cleft nose, (e) median cleft prolabium2 and premaxilla,3 (f) median cleft secondary palate. In addition to these abnormalities, some patients have frontal lipomas, dermoids, or teratomas. Of this group of anomalies, orbital hypertelorism, cranium bifidum occultum frontalis, median cleft nose, and median cleft prolabium and premaxilla were considered basic in further subdividing cases into four facial types. This classification is based on a study of 25 cases, including 8 personal ones (1). The findings in Type 1 fades (3 of 25 cases) are: (a) orbital hypertelorism, (b) complete cleft of the nose, (c) absence or marked hypoplasia of a cleft prolabium and premaxilla, and (d) cranium bifidum occultum frontalis. In addition, in this facial type the palatine processes of the maxillary bones (secondary palate) may be widely separated. Case I: U. M., a 1-month-old Negro male, had the most severe form of the median cleft face syndrome encountered and probably the most severe form compatible with life (Fig. 1). Evaluation at thirteen months of age suggested mild mental retardation. Skull roentgenograms disclosed a wide cleft (50 mm) between the bony orbits, maxillary bones, and ethmoid elements, with the cleft extending posteriorly to the sphenoid bone. The primary direction of the orbital axes was lateral. The premaxilla and palatine processes of the maxillary bones could not be identified. The anterior clinoid processes and the sella turcica were normal in appearance. Ossification of the frontal bones was deficient above the cleft. The head size was normal. Case II: C. H. was a 1-day-old male infant. Frontal and lateral skull roentgenograms showed marked orbital hypertelorism (31 mm) (Fig. 2). The maxillary bones were separated with the interspace bridged by “ethmoid filler.” The cleft in the secondary palate extended superiorly into the ethmoid area. The premaxilla could not be identified. There was an extensive defect in ossification of the frontal bones with a median bar of bone. The anterior clinoid processes and the sella turcica appeared normal.

Bilateral Curving of the Terminal Phalanges of the Little Fingers

Two cases of spontaneous bilateral volar-radial deviation of the terminal phalanges of the little fingers (Kirner's disorder) are reported. The first case was accompanied by digital pain, and the second was associated with progressive myositis ossificans. Typically, the disorder occurs in the prepubescent child. The clinical course and roentgenographic appearance suggest that the lesion is the result of a defect in enchondral ossification on the volar aspect of the epiphyseal plate and slipping of the epiphysis.

The Development of the Inner Ear in Mice Homozygous for Shaker-with-Syndactylism

ABSTRACT A reinvestigation of the effects of the gene sy on the inner ear showed that the first abnormalities appear several days earlier than had hitherto been believed, and that they concern the periotic labyrinth and not the otic labyrinth. An excessive amount of mesenchymal tissue is laid down round certain, if not all, parts of the otic labyrinth in 13-day embryos, and as the periotic labyrinth is derived from this tissue it is abnormal. The abnormalities of the otic labyrinth appear at least 4 days later, and consist in a dedifferentiation of the epithelium and its penetration by the periotic mesenchymal tissue. As the otic labyrinth is surrounded by the periotic labyrinth, it is believed that the abnormalities of the former are consequent upon those of the latter, although the underlying mechanism is not understood. A possible connection has been suggested between the three major effects of the gene sy, namely, abnormalities of the inner ear, syndactylism, and defects of ossification involving the whole skeleton.

ON THE OSSIFICATION DEFECT IN LATHYRISM.

ON THE OSSIFICATION DEFECT IN LATHYRISM.

Progeria, a pathologic study

S I N c e . Gilford 1 introduced the term progeria in 1904 fewer than 30 typical cases have been reported. A thorough review of the literature with full description of the syndrome has been made by Thomson and Forfar in 19502 and by Gabr in 19547 Several cases have been described subsequently. 4-~~ The syndrome is characterized by stunted growth associated with an appearance of premature senility and a normal mentality (the old wizened dwarf). The disease first manifests itself at the end of the first year of life by causing an arrest of growth in both weight and in height, loss of hair, loss of subcutaneous fat with subsequent wasting, and relative enlargement of the joints with limitation of their movement. The face appears small with a receding chin, overcrowded teeth, and prominent eyes with no eyelashes or eyebrows. The skin is thin and the nails are atrophied; the hands with their flexed fingers and enlarged joints simulate the hands of an old person. Skeletal .changes, which include thin bones, small clavicles, defective ossification of the skull, and coxa valga, are often present. As the child grows older arteriosclerotic changes develop, and the patient usually dies in the second decade