Computed tomography (CT), magnetic resonance imaging (MRI), and adrenal vein sampling (AVS) are used to distinguish unilateral from bilateral increased aldosterone secretion as a cause of primary ...aldosteronism. This distinction is crucial because unilateral primary aldosteronism can be treated surgically, whereas bilateral primary aldosteronism should be treated medically.
To determine the proportion of patients with primary aldosteronism whose CT or MRI results with regard to unilateral or bilateral adrenal abnormality agreed or did not agree with those of AVS.
PubMed, MEDLINE, EMBASE, and Cochrane Library, 1977 to April 2009.
Studies describing adults with primary aldosteronism who underwent CT/MRI and AVS were included. Of 472 initially identified studies, 38 met the selection criteria; extractable data were available for 950 patients.
The CT/MRI result was considered accurate when AVS showed unilaterally increased aldosterone secretion on the same side as the abnormality seen on CT/MRI or when AVS showed symmetric aldosterone secretion and CT/MRI revealed bilateral or no unilateral abnormality.
In 37.8% of patients (359 of 950), CT/MRI results did not agree with AVS results. If only CT/MRI results had been used to determine lateralization of an adrenal abnormality, inappropriate adrenalectomy would have occurred in 14.6% of patients (where AVS showed a bilateral problem), inappropriate exclusion from adrenalectomy would have occurred in 19.1% (where AVS showed unilateral secretion), and adrenalectomy on the wrong side would have occurred in 3.9% (where AVS showed aldosterone secretion on the opposite side).
The lack of follow-up data in the included articles made it impossible to confirm that adrenalectomies were performed appropriately.
When AVS is used as the criterion standard test for diagnosing laterality of aldosterone secretion in patients with primary aldosteronism, CT/MRI misdiagnosed the cause of primary aldosteronism in 37.8% of patients. Relying only on CT/MRI may lead to inappropriate treatment of patients with primary aldosteronism.
A large family is described with gray platelet syndrome due to an autosomal dominant inheritance pattern related to a dominant-negative mutation in
GFI1B
. The mutation leads to a loss in gene ...repression during megakaryocyte development.
Platelets are formed through fragmentation of megakaryocytes that reside in the bone marrow.
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Platelet alpha granules, which are by far the most abundant platelet organelles, store proteins that stimulate platelet adhesiveness, hemostasis, and wound healing.
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,
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The gray platelet syndrome is an inherited bleeding disorder characterized by defective production of alpha granules.
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Patients with this syndrome have reduced numbers of larger-than-normal platelets, and on light microscopy these platelets have a typical gray appearance caused by the lack of alpha granules. For a final diagnosis, the lack of alpha granules must be confirmed by means of electron microscopy.
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Clinically, . . .
Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors ...of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Untreated congenital hypothyroidism leads to severe developmental difficulties. The authors of this report sought to identify defects in the thyroid oxidase system in infants with ...iodide-organification defects because two proteins, thyroid oxidase 1 and thyroid oxidase 2, are involved in that process. Biallelic loss-of-function mutations in
THOX2,
the gene for thyroid oxidase 2, were found in one patient with permanent congenital hypothyroidism, and monoallelic mutations were found in three patients with transient congenital hypothyroidism.
Congenital hypothyroidism is the most common congenital endocrine disorder, affecting 1 in every 3000 to 4000 newborns. Neonatal screening programs allow its early detection and treatment, thus preventing the cognitive and motor impairment caused by lack of thyroid hormone during the early postnatal phase of brain development.
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The need for thyroid hormone supplementation can be permanent or transient.
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The cause of permanent congenital hypothyroidism of primary origin has been linked to defects in proteins involved in the synthesis of thyroid hormones
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and to defects in transcription factors involved in the development of the thyroid gland.
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–
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Overall, these cases . . .
N-Acetylglucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential and dynamic post-translational modification. The O-GlcNAc modification is present on numerous nuclear ...and cytosolic proteins and has been implicated in essential cellular functions such as signaling and gene expression. Accordingly, altered levels of protein O-GlcNAcylation have been associated with developmental defects and neurodegeneration. However, mutations in the OGT gene have not yet been functionally confirmed in humans. Here, we report on two hemizygous mutations in OGT in individuals with X-linked intellectual disability (XLID) and dysmorphic features: one missense mutation (p.Arg284Pro) and one mutation leading to a splicing defect (c.463–6T>G). Both mutations reside in the tetratricopeptide repeats of OGT that are essential for substrate recognition. We observed slightly reduced levels of OGT protein and reduced levels of its opposing enzyme O-GlcNAcase in both patient-derived fibroblasts, but global O-GlcNAc levels appeared to be unaffected. Our data suggest that mutant cells attempt to maintain global O-GlcNAcylation by down-regulating O-GlcNAcase expression. We also found that the c.463–6T>G mutation leads to aberrant mRNA splicing, but no stable truncated protein was detected in the corresponding patient-derived fibroblasts. Recombinant OGT bearing the p.Arg284Pro mutation was prone to unfolding and exhibited reduced glycosylation activity against a complex array of glycosylation substrates and proteolytic processing of the transcription factor host cell factor 1, which is also encoded by an XLID-associated gene. We conclude that defects in O-GlcNAc homeostasis and host cell factor 1 proteolysis may play roles in mediation of XLID in individuals with OGT mutations.
Context: Patients with thyroidal congenital hypothyroidism (CH-T) born in The Netherlands in 1981–1982 showed persistent intellectual and motor deficits during childhood and adulthood, despite ...initiation of T4 supplementation at a median age of 28 d after birth.
Objective: The present study examined whether advancement of treatment initiation to 20 d had resulted in improved cognitive and motor outcome.
Design/Setting/Patients: In 82 Dutch CH-T patients, born in 1992 to 1993 and treated at a median age of 20 d (mean, 22 d; range, 2–73 d), cognitive and motor outcome was assessed (mean age, 10.5 yr; range, 9.6–11.4 yr). Severity of CH-T was classified according to pretreatment free T4 concentration.
Main Outcome Measure: Cognitive and motor outcome of the 1992–1993 cohort in comparison to the 1981 to 1982 cohort was the main outcome measure.
Results: Patients with severe CH-T had lower full-scale (93.7), verbal (94.9), and performance (93.9) IQ scores than the normative population (P < 0.05), whereas IQ scores of patients with moderate and mild CH-T were comparable to those of the normative population. In all three severity subgroups, significant motor problems were observed, most pronounced in the severe CH-T group. No correlations were found between starting day of treatment and IQ or motor outcome.
Conclusions: Essentially, findings from the 1992–1993 cohort were similar to those of the 1981–1982 cohort. Apparently, advancing initiation of T4 supplementation from 28 to 20 d after birth did not result in improved cognitive or motor outcome in CH-T patients.
ABSTRACT
At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized ...world. Molecular confirmation of the diagnosis is increasingly important for gene‐tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor‐intensive. To circumvent these problems, we developed a TAA gene panel for next‐generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation‐dependent probe amplification identified large deletions in six of the remaining samples, whereas false‐negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes.
Thoracic aortic aneurysm (TAA) is an important cause of death in the industrialized world. Both syndromic and non‐syndromic forms of TAA exists and to date 14 causative genes have been identified. To shorten the turnaround time, increase mutation‐uptake and reduce the overall cost of molecular testing, we developed a next generation sequencing panel of 14 TAA genes (ACTA2, COL3A1, EFEMP2, FBN1, FLNA, MYH11, MYLK, NOTCH1, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1 and TGFBR2) that can be tested simultaneously.
The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in ...cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults.
Much worldwide attention is given to the adverse effects of maternal Graves’ disease on the fetal and neonatal thyroid and its function. However, reports concerning the adverse effects of maternal ...Graves’ disease on the pituitary function, illustrated by the development of central congenital hypothyroidism (CCH) in the offspring of these mothers, are scarce. We studied thyroid hormone determinants of 18 children with CCH born to mothers with Graves’ disease. Nine mothers were diagnosed after pregnancy, the majority after their children were detected with CCH by neonatal screening. Four mothers were diagnosed during pregnancy and treated with antithyroid drugs since diagnosis. Another four mothers were diagnosed before pregnancy, but they used antithyroid drugs irregularly; free T4 concentrations less than 1.7 ng/dl (<22 pmol/liter) were not encountered during pregnancy. All neonates had decreased plasma free T4 concentrations (range 0.3–0.9 ng/dl, 3.9–11.5 pmol/liter); plasma TSH ranged between 0.1 and 6.6 mU/liter. TRH tests showed pituitary dysfunction. Seventeen children needed T4 supplementation. Because all mothers were insufficiently treated during pregnancy, it is hypothesized that a hyperthyroid fetal environment impaired maturation of the fetal hypothalamic-pituitary-thyroid system. The frequent occurrence of this type of CCH (estimated incidence 1:35,000) warrants early detection and treatment to minimize the risk of cerebral damage. A T4-based screening program appears useful in detecting this type of CCH. However, the preferential and presumably best strategy to prevent CCH caused by maternal Graves’ disease is preserving euthyroidism throughout pregnancy.
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