Delayed Bone Development Research Articles

A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion

Genomic rearrangements are an increasingly recognized mechanism of human phenotypic variation and susceptibility to disease. Sotos syndrome is characterized by overgrowth, macrocephaly, developmental delay and advanced osseous maturation. Haploinsufficiency of NSD1, caused by inactivating point mutations or deletion copy number variants, is the only known cause of Sotos syndrome. A recurrent 2 Mb deletion has been described with variable frequency in different populations. In this study, we report two individuals of different ethnic and geographical backgrounds, with duplications reciprocal to the common Sotos syndrome deletion. Our findings provide evidence for the existence of a novel syndrome of short stature, microcephaly, delayed bone development, speech delay and mild or absent facial dysmorphism. The phenotype is remarkably opposite to that of Sotos syndrome, suggesting a role for NSD1 in the regulation of somatic growth in humans.

Akt1 Controls Insulin-Driven VEGF Biosynthesis from Keratinocytes: Implications for Normal and Diabetes-Impaired Skin Repair in Mice

Here we investigated the potential role of protein kinase B (Akt) in normal or diabetes-impaired wound healing in mice. Interestingly, Akt1 was predominant in skin, wound tissue, and human keratinocytes cell line. Acute skin repair was characterized by an increase of Akt1 phosphorylation in wound margin keratinocytes. By contrast, phosphorylated Akt1 was nearly completely absent and paralleled by a poor phosphorylation of the eucaryotic initiation factor 4E-binding protein 1 (4E-BP1) and reduced levels of vascular endothelial growth factor (VEGF) protein in chronic wounds of diabetic ob/ob mice. Inhibition of the phosphatidyl-inositol-3 kinase/Akt pathway by wortmannin and specific abrogation of Akt1 protein using small-interfering RNA revealed a regulatory function of Akt1 in insulin-mediated VEGF biosynthesis in keratinocytes. Insulin-induced VEGF protein biosynthesis in keratinocytes was mediated by Akt1 from a constitutive VEGF-encoding mRNA pool at the posttranscriptional level through a downstream phosphorylation 4E-BP1. Moreover, transfection experiments introducing a constitutively active mutant of Akt1 into keratinocytes revealed the mammalian target of rapamycin kinase as a downstream mediator of Akt1-linked 4E-BP1 phosphorylation and translational control. Our data suggest that the endocrine hormone insulin contributes to VEGF release in skin wounds through an Akt1-mediated posttranscriptional mechanism in keratinocytes.

SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth

SummaryCell growth (accumulation of mass) needs to be coordinated with metabolic processes that are required for the synthesis of macromolecules. The PI3-kinase/Akt signaling pathway induces cell growth via activation of complex 1 of the target of rapamycin (TORC1). Here we show that Akt-dependent lipogenesis requires mTORC1 activity. Furthermore, nuclear accumulation of the mature form of the sterol responsive element binding protein (SREBP1) and expression of SREBP target genes was blocked by the mTORC1 inhibitor rapamycin. We also show that silencing of SREBP blocks Akt-dependent lipogenesis and attenuates the increase in cell size in response to Akt activation in vitro. Silencing of dSREBP in flies caused a reduction in cell and organ size and blocked the induction of cell growth by dPI3K. Our results suggest that the PI3K/Akt/TOR pathway regulates protein and lipid biosynthesis in an orchestrated manner and that both processes are required for cell growth.

Coffin-Lowry Syndrome: Findings and I dental treatment

Coffin-Lowry Syndrome is characterized by mental retardation, skeletal abnormalities, delayed bone development, short stature, tapered fingers, large ears, orbital hypertelorism, anteverted nares, and a prominent frontal region. This inherited disorder is x-linked and is genetically mapped to the Xp22.2 chromosomal region. This report presents the dental findings of three male members of the same family: an older brother and younger identical twins; all three were first examined at age 10. The father's family came from North Africa and the mother's from Eastern Europe. In addition to the reported typical characteristics of Coffin-Lowry Syndrome, a number of specific dental findings were found in all of the brothers, namely, maxillary protrusion, open bite, two-year retardation in age of eruption, agenesis of the permanent mandibular central incisors in all of the brothers, and a marked oligodontia in the oldest. Despite difficulties in management, the dental treatment for caries and gingivitis could be completed on the brothers without sedation.

Comparison among dental, skeletal and chronological development in HIV-positive children: a radiographic study

The goal of this study was to evaluate skeletal, dental and chronological development in an HIV-positive group of children, as compared with a control group, during a four-year period. Panoramic radiographs and hand and wrist radiographs of 60 children were taken. The children, of both sexes, aged 5 years and 2 months to 15 years and 5 months, were selected as follows: 30 HIV-positive volunteers who had acquired the disease vertically, and 30 volunteers who did not present the HIV infection or any other systemic disease. All radiographs were technically standardized and analyzed according to criteria established by Nolla (dental age), Greulich and Pyle (bone age), and Eklöf and Ringertz (bone age). The results were submitted to Student's t-test at a 5% level of significance. Based on the comparison between the chronological age and the dental or the skeletal age, significant differences were observed between HIV-positive and HIV-negative children, both in 1999 and in 2003 (p < or = 0.05). Considering the results obtained with the methodology used, it was concluded that HIV-positive children of both sexes presented delayed bone development despite the administration of antiretroviral drugs, and that HIV-positive female children presented younger dental ages compared with their chronological ages in 1999 and in 2003; and HIV-positive males, in 1999.

Developmental signals in skin morphogenesis.

Developmental signals in skin morphogenesis.

Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2.

To elucidate the functions of the serine/threonine kinase Akt/PKB in vivo, we generated mice lacking both akt1 and akt2 genes. Akt1/Akt2 double-knockout (DKO) mice exhibit severe growth deficiency and die shortly after birth. These mice display impaired skin development because of a proliferation defect, severe skeletal muscle atrophy because of a marked decrease in individual muscle cell size, and impaired bone development. These defects are strikingly similar to the phenotypes of IGF-1 receptor-deficient mice and suggest that Akt may serve as the most critical downstream effector of the IGF-1 receptor during development. In addition, Akt1/Akt2 DKO mice display impeded adipogenesis. Specifically, Akt1 and Akt2 are required for the induced expression of PPARgamma, the master regulator of adipogenesis, establishing a new essential role for Akt in adipocyte differentiation. Overall, the combined deletion of Akt1 and Akt2 establishes in vivo roles for Akt in cell proliferation, growth, and differentiation. These functions of Akt were uncovered despite the observed lower level of Akt activity mediated by Akt3 in Akt1/Akt2 DKO cells, suggesting that a critical threshold level of Akt activity is required to maintain normal cell proliferation, growth, and differentiation.

EFFECT OF THYROID HORMONE ON GROWTH: Lessons from the Syndrome of Resistance to Thyroid Hormone

Thyroid hormone deprivation results in deleterious effects on bone growth. The delayed bone development is mediated by a direct effect of thyroid hormone on bone and an indirect effect of the hormone on GH release and IGF-1 action. Both TR alpha and TR beta are expressed in bone cells. To examine the role of TR beta on bone, we have reviewed the growth abnormalities in the human syndrome of RTH caused by mutations in the TR beta gene. The mutant TR beta reduces the tissue responsiveness to thyroid hormone, producing in some tissues variable degrees of thyroid hormone deprivation. With regard to bone, relative thyroid hormone deficiency caused by the mutant TR beta produces short stature and delayed bone growth but does not attenuate growth to the extent that absolute thyroid hormone deficiency does. These observations indicate that an intact TR beta is required for normal bone development and growth.

Role of insulin-like growth factors in embryonic and postnatal growth

A developmental analysis of growth kinetics in mouse embryos carrying null mutations of the genes encoding insulin-like growth factor I (IGF-I), IGF-II, and the type 1 IGF receptor (IGF1R), alone or in combination, defined the onset of mutational effects leading to growth deficiency and indicated that between embryonic days 11.0 and 12.5, IGF1R serves only the in vivo mitogenic signaling of IGF-II. From E13.5 onward, IGF1R interacts with both IGF-I and IGF-II, while IGF-II recognizes an additional unknown receptor (XR). In contrast with the embryo proper, placental growth is served exclusively by an IGF-II-XR interaction. Additional genetic data suggested that the type 2IGF/mannose 6-phosphate receptor is an unlikely candidate for XR. Postnatal growth curves indicated that surviving Igf-1(-/-) mutants, which are infertile and exhibit delayed bone development, continue to grow with a retarded rate after birth in comparison with wild-type littermates and become 30% of normal weight as adults.

Perthesʼ Disease and Posterior Lumbosacral Union

Delayed bone development is common in Perthes' disease, and affected children are usually smaller than normal. Somatosensory evoked potentials (SEP) studied in 25 cases of Perthes' disease were normal. Fifty-four patients with active or healed Perthes' disease were examined. Every child aged less than 8 years showed failure of posterior lumbar and/or sacral fusion. With growth, fusion increased so that at age 14 years 50% had a normal fusion and 50% had spina bifida occulta. At age greater than 16 years, the incidence was similar to that in the general population. In Perthes' disease, growth in fusion of the lumbosacral elements is delayed.

Delayed bone development in epileptic children assessed by microdensitometer.

Bone development of metacarpal bones was assessed by microdensitometer analysis of hand X-rays from 101 epileptic outpatients. Most of the patients were treated with two or three anticonvulsant drugs; however, 27 patients were treated with only one. A significantly larger number of patients showed a delay in bone development of 2 or more years when compared with either handicapped or normal control children. In epileptic children, physical activity and the duration of anticonvulsant therapy were correlated with bone development. Patients with delayed bone development had reduced levels of serum 25-OH-D (p less than 0.005) and elevated levels of 1,25-(OH)2D (p less than 0.01). Microdensitometer analysis of metacarpal bone radiographs is useful for detecting mild impairment of bone in groups of epileptic children.

CONGENITAL EUTHYROID GOITRE AND PARTIAL PERIPHERAL RESISTANCE TO THYROID HORMONES

A woman aged 25, who had had goitre at birth and had undergone thyroidectomy twice for non-toxic goitre during childhood, was entirely euthyroid. Concentrations of protein-bound iodine, total and free thyroxine, and total triiodothyronine were about twice the normal upper level, and the daily turnover of thyroxine was about doubled, but the level of thyrotrophin in the blood and the responses of thyrotrophin-stimulating hormone and triiodothyronine to stimulation with thyrotrophin-releasing hormone were normal. These findings are compatible with partial resistance to thyroid hormones in the peripheral tissues, including the anterior pituitary. The syndrome differs from the peripheral resistance described by other workers, with deaf-mutism, delayed bone development, and stippled epiphyses. It thus represents a different type of unresponsiveness to thyroid hormones.

Un Cas de Nanisme Avec Insuffisance Ovarienne Totale et Hypersécrétion D’Hormone Gonadotrope

SummaryTypical case of Turner’s syndrom is reported. Diagnosis is based on the following signs :1° dwarfism ;2° ovarial agenesia ;3° congenital abnormalities and specially a webbed neck.1° Dwarfism is harmonious ; it seems that prepuberty growth has been delayed. Lightly delayed bone development is shown by XRay study. Neither starvation, nor a definite disease of the bones, nor thyroid, nor pituitary disturbances account for dwarfism. Two other possible factors are suggested : either congenital abnormalities of the epiphyseal cartilage or lack of œstrogenic factor.2° Examination of vaginal smears reveals a picture in agreement with the diagnosis of ovarial agenesia. Hypopituitarism is ruled out by an increased urinary excretion of folliculin secreting hormone : a fact that may be given as a necessary feature of the disease.3° Other abnormalities observed in this case are : webbed neck, epicanthus, nœvi and supernumerary teeth.Oestrogens given by mouth resulted in increased feminisation of the patient features.