Idiopathic Growth Retardation Research Articles

Abstract PR3: The BLM helicase facilitates RNA polymerase l-mediated ribosomal RNA transcription

Abstract Bloom's syndrome (BS) is an autosomal recessive disorder that is invariably characterized by cancer predisposition and idiopathic growth retardation. The BLM helicase, mutations of which lead to BS, localizes to the nucleolus of the cell, the site of RNA polymerase l-mediated ribosomal RNA (rRNA) transcription. rRNA transcription is fundamental for ribosome biogenesis and therefore protein synthesis, cellular growth and proliferation; its inhibition limits cellular growth and proliferation as well as bodily growth. Disorders with defective ribosome biogenesis, such as Diamond-Blackfan anemia and Shwachman-Diamond syndrome, display similar cancer predisposition and growth abnormalities to BS. The objective of this study was to investigate a potential mechanism underlying the proportional dwarfism of BS. We tested the hypothesis that the BLM helicase facilitates rRNA transcription as a component of an RNA polymerase I-associated complex, which when deficient has the potential to lead to proportional dwarfism. We report that nucleolar BLM facilitates RNA polymerase I-mediated rRNA transcription using H3-uridine pulse-chase assays and nuclear run-on assays in cells with an innate or experimentally induced BLM deficiency. In vitro helicase assays demonstrate that BLM unwinds GC-rich hybrid RNA/DNA nucleic acid substrates predicted to form in the nucleolus during rRNA transcription; the persistence of such structures inhibits progression of the RNA polymerase I transcription complex. Immunofluorescence studies using actinomycin D at a concentration that inhibits RNA polymerase I demonstrate the dependence of BLM nucleolar localization upon ongoing RNA polymerase l-mediated rRNA transcription. Finally, in vivo protein co-immunoprecipitation shows that BLM physically associates with RNA polymerase I in the nucleolus. These studies suggest that nucleolar BLM interacts with RNA polymerase I and facilitates rRNA transcription by modulating rDNA structure. Given the intricate relationship between rDNA metabolism and growth, our data may help to understand the etiology of the proportional dwarfism in Bloom's syndrome. Furthermore, this work provides greater understanding of the mechanisms regulating rRNA transcription and ribosome biogenesis, processes currently being exploited in cancer therapeutics. This abstract is also presented as Poster B34. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR3.

Clinical syndromes associated with the shox gene

Growth is a complex process, which is influenced by a huge number of factors at all stages of development starting from the prenatal. Up to 3% of the population suffers from stunting, caused by various reasons. When examining patients with growth retardation, differential diagnosis is usually carried out between pituitary dwarfism, hypothyroidism, systemic diseases, chromosomal disorders, various forms of chondrodysplasias, psychosocial disorders and idiopathic growth retardation, the frequency of which among all forms of short stature heights reaches 80%

SHOX gene mutations and deletions in dyschondrosteosis or Leri-Weill syndrome.

Dyschondrosteosis is an autosomal dominant form of mesomelic dysplasia that is often combined with a deformity of the forearms called Madelung deformity. Based on the observation of X-Y translocations (p22,q12) in patients with dyschondrosteosis, the authors tested the pseudoautosomal region in eight affected families and showed linkage of the dyschondrosteosis gene to a microsatellite DNA marker at the DXYS233 locus (Zmax = 6.26 at theta = 0). Since the short stature homeobox-containing gene (SHOX) involved in idiopathic growth retardation and possibly Turner syndrome maps to this region, SHOX was regarded as a strong candidate gene for dyschondrosteosis. This article reports the detection of large-scale SHOX deletions in seven of the eight families and a nonsense mutation of SHOX in the remaining family affected with dyschondrosteosis. Additional evidence suggests that Langer mesomelic dwarfism results from homozygous mutations at the genetic locus responsible for dyschondrosteosis.

Can we escape our genetic destiny?

During 1998, progress has been made in the identification of specific genes that are responsible for, or predispose to, endocrine disorders. Several genetic abnormalities of the thyroid have been described, such as two new mutations in exon 10 of the thyrotropin-receptor gene, resulting in a clinical picture of thyroid hypoplasia and congenital hypothyroidism as well as germ-line neo-mutations in the extracellular portion of the thyrotropin receptor, leading to an opposite clinical picture of severe congenital hyperthyroidism. In addition to previously disovered mutations, new mutations in the PIT-I and the PROP-I gene, responsible for combined pituitary hormone deficiency, have been reported. In patients with septo-optic dysplasia a mutation in the homeobox gene HESXI/Hesxl was found, indicating that the gene plays an important role in the development of Will the forebrain, midline, and pituitary. Growth hormone insensitivity syndrome (GHIS) is now associated with'a broad spectrum of mutations of the GH receptor gene. Woods and colleagues showed that GHIS is, a highly variable condition--from severely affected patients with classical GH insensitivity to a larger group of with idiopathic short stature. Other genetic and/or environmental factors must, therefore, contribute to the phenotype. Intriguing results were found when families with LeriWeill dyschondrosteosis (LWD), a dominant inherited skeletal dysplasia characterised by disproportionate short stature with mesomelic limb shortening, were studied. Various mutations of the short stature homeoboxcontaining gene (SHOX) were found in patients with LWD. These S H O X mutations, however, have also been found in idiopathic growth retardation and Turner (XO) short stature, conditions without bone dysplasia. One explanation is that loss of other genes from the nonpseudoautosomal region of the X chromosome in Turner 's syndrome may mask the full phenotype of S H O X haploinsufficiency. The variable expression in families segretating for a S H O X deletion or mutation suggests that there may be a modifying gene, or genes, on an autosome or on the X chromosome itself, and background genetic effects and environmental factors may also play a role. The mentioned genetic disorders are just examples. Reports about various mutations have appeared in 1998, indicating that in the coming, years many endocrine disorders will be found to be genetically determined. Research in the field of obesity and leptin has progressed. In a large population of massively obese people, however, no mutations of the leptin receptor were found. Feeding behaviour and caloric balance are also modified by neuronal effectors such as neuropeptide Y,

SHOX mutations in dyschondrosteosis (Leri-Weill syndrome).

Dyschondrosteosis (DCS) is an autosomal dominant form of mesomelic dysplasia with deformity of the forearm (Madelung deformity; ref. 3). Based on the observation of XY translocations (p22,q12; refs 4-6) in DCS patients, we tested the pseudoautosomal region in eight families with DCS and showed linkage of the DCS gene to a microsatellite DNA marker at the DXYS233 locus (Zmax=6.26 at theta=0). The short stature homeobox-containing gene (SHOX), involved in idiopathic growth retardation and possibly Turner short stature, maps to this region and was therefore regarded as a strong candidate gene in DCS. Here, we report large-scale deletions (in seven families) and a nonsense mutation (in one family) of SHOX in patients with DCS and show that Langer mesomelic dwarfism results from homozygous mutations at the DCS locus.

Atrial natriuretic factor, digoxin-like immunoreactive substance, norepinephrine, epinephrine, and plasma renin activity in human fetuses and their alteration by fetal disease

We measured five hormones presumably involved in fetal homeostasis in specimens obtained by cordocentesis for clinical indications from 106 fetuses. Norms for atrial natriuretic factor, digoxin-like immunoreactive substance, plasma renin activity, norepinephrine, and epinephrine were derived from fetuses ultimately shown to be free of detectable abnormality. Atrial natriuretic factor, digoxin-like immunoreactive substance, and plasma renin activity were unrelated to umbilical vessel source or gestational age. Digoxin-like immunoreactive substance was directly related to Pco2 (r = 0.63, p = 0.02). Digoxin-like immunoreactive substance level was elevated in all fetal disease states studied except isoimmunization. The level of atrial natriuretic factor was elevated in fetuses with immune hydrops (NS). Norepinephrine and epinephrine levels were higher in the umbilical artery than in the vein (p = 0.05 and 0.006, respectively). There was a significant correlation between norepinephrine and gestational age in normal fetuses (r = 0.7637, p < 0.025) and between both catecholamines and many of the respiratory blood gas measurements, with pH and Pco2 being the major determinants. Most disease states were associated with an elevated norepinephrine concentration. There was a negative correlation between plasma renin activity and base deficit (p < 0.0001). Plasma renin activity was elevated in fetuses with idiopathic growth retardation and nonimmune hydrops (p < 0.05 for each). In summary, fetal homeostasis as reflected by these five hormones was altered by a variety of disorders. With these baseline values the effects of direct or indirect fetal therapy can begin to be studied.

Inflammatory bowel disease in children and adolescents

Ulcerative colitis and Crohn's disease are significant childhood illnesses. With their many extraintestinal manifestations, they may masquerade as fever of unknown etiology, arthritis, anorexia nervosa, growth hormone deficiency, collagen-vascular disease, idiopathic growth retardation and even irritable bowel syndrome of childhood. In any child who presents with growth failure and/or chronic abdominal pain with fever or weight loss, the diagnosis of inflammatory bowel disease must be considered. As in any other chronic disease of childhood, long-term management will often challenge the physician emotionally and intellectually. As the etiology is yet unknown and a definitive cure is lacking, proper treatment depends on optimal medical and surgical management and supportive care.

THE EFFECT OF METHANDROSTENOLONE ON PITUITARY GROWTH HORMONE SECRETION IN PREPUBERTAL CHILDREN

SUMMARYThe effect of methandrostenolone on plasma growth hormone levels was studied in twenty‐two apparently healthy prepubertal children (nineteen males and three females) with idiopathic growth retardation, following insulin hypoglycaemia (eight children) or arginine infusion (fourteen children). The tests were performed before and after 5 days or 34 months of peroral administration of methandrostenolone (0.1 54.33 or 0.03‐0.05 mg/kg/day, respectively).

Renal excretion of hydrogen ion in children with idiopathic growth retardation

Mild, compensated metabolic acidosis was demonstrated in a group of children with growth retardation of undetermined etiology. In response to administration of a single large dose of ammonium chloride, urinary acidification was normal, but there was a limitation in the rate of excretion of hydrogen ion as titratable acid and as ammonium. Since these children had no other evidence of renal impairment, it is postulated that growth retardation per se modifies renal regulation of acid-base balance through effects on both phosphorus and ammonia metabolism.