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      A Homozygous L299P Mutation in the CYP11B1 Gene Leads to Complete Virilization in 46,XX Individuals with 11-Beta-Hydroxylase Deficiency

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          Background/Aim: 11-β-hydroxylase deficiency (11βOHD) is caused by CYP11B1 gene defects and leads to congenital adrenal hyperplasia associated with hypertension. Recently, a novel L299P mutation has been described in a compound heterozygous male individual. We observed two 46,XX siblings with a homozygous L299P mutation and investigated the functional properties of this CYP11B1 variant. Patients: The index patient from a consanguineous Turkish family showed complete external virilization and was diagnosed incidentally at the age of 19 months during hospital admission for severe combined bacterial (urosepsis) and viral (CMV and EBV) infection. The younger sibling was diagnosed at the age of 5 months. Their genital phenotype was identical and both demonstrated borderline elevated blood pressure. Results: Biochemical findings revealed 11βOHD. A homozygous L299P mutation of the CYP11B1 gene was detected. In vitro expression studies performed in HCT116 cells showed a markedly decreased CYP11B1 activity in the L299P mutant (1.6 ± 0.8%) for the conversion of 11-deoxycortisol to cortisol. Conclusions: Our study provides clear data on the functional properties and clinical phenotype in 46,XX individuals homozygous for this point mutation. Adrenal insufficiency might have contributed to the severe infectious disease that was present in the index patient at diagnosis.

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          Most cited references 10

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          A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension.

          Glucocorticoid-remediable aldosteronism (GRA), an autosomal dominant disorder, is characterized by hypertension with variable hyperaldosteronism and by high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, which are all under control of adrenocorticotropic hormone and suppressible by glucocorticoids. These abnormalities could result from ectopic expression of aldosterone synthase, which is normally expressed only in adrenal glomerulosa, in the adrenal fasciculata. Genes encoding aldosterone synthase and steroid 11 beta-hydroxylase (expressed in both adrenal fasciculata and glomerulosa), which are 95% identical and lie on chromosome 8q (refs 7, 10), are therefore candidate genes for GRA. Here we demonstrate complete linkage of GRA in a large kindred to a gene duplication arising from unequal crossing over, fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase (maximum lod score 5.23 for complete linkage, odds ratio of 170,000:1). This mutation can account for all the physiological abnormalities of GRA. Our result represents the demonstration of a mutation causing hypertension in otherwise phenotypically normal animals or humans.
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            Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study.

            Within the last few years, increasing evidence of relative adrenal insufficiency in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation, 40 patients with septic shock were randomized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 (n = 20) or placebo (n = 20), followed by the opposite medication until Day 6. Hydrocortisone infusion induced an increase of mean arterial pressure, systemic vascular resistance, and a decline of heart rate, cardiac index, and norepinephrine requirement. A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support. The inflammatory response (interleukin-6 and interleukin-8), endothelial (soluble E-selectin) and neutrophil activation (expression of CD11b, CD64), and antiinflammatory response (soluble tumor necrosis factor receptors I and II and interleukin-10) were attenuated. In peripheral blood monocytes, human leukocyte antigen-DR expression was only slightly depressed, whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects. In conclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression.
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              CYP11B1 mutations causing congenital adrenal hyperplasia due to 11 beta- hydroxylase deficiency

               S Geley (1996)

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                September 2008
                29 July 2008
                : 70
                : 3
                : 145-149
                aDepartment of Pediatrics, Medical University of Vienna, Vienna, Austria, bInstitute of Biochemistry, Saarland University, Saarbrucken, cLaboratory for Molecular Genetics, Endocrine Practice, Heidelberg, Germany
                137659 Horm Res 2008;70:145–149
                © 2008 S. Karger AG, Basel

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                Figures: 1, Tables: 1, References: 21, Pages: 5
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