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      A case report: Familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis

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          Abstract

          Background

          Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency in the presence of normal plasma renin and aldosterone level. Focal segmental glomerulosclerosis (FSGS) is a form of glomerular disease associated with proteinuria and nephritic syndrome. This is the first case of familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis.

          Case presentation

          An eight month old boy presented with increased genital pigmentation. Initial investigation revealed that he was glucocorticoid deficient and was started on hydrocortisone and fludrocortisone with a diagnosis of primary adrenal insufficiency. Later fludrocortisone was withdrawn and he was diagnosed to have isolated glucocorticoid deficiency. He later developed focal segmental glomerulosclerosis for which he underwent renal transplantation at the age of five years. Now at the age of twelve years, this boy is doing well on hydrocortisone treatment. His two siblings and a first degree cousin also had isolated glucocorticoid deficiency. One of the above two siblings died due to renal failure secondary to focal segmental glomerulosclerosis.

          Conclusion

          Patients with familial glucocorticoid deficiency should be carefully followed for development of features of nephrotic syndrome.

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          Most cited references15

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          Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2

          Context Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder as a result of mutation in genes encoding either the ACTH receptor [melanocortin 2 receptor (MC2R)] or its accessory protein [melanocortin 2 receptor accessory protein (MRAP)[. The disorder is known as FGD type 1 and 2, respectively. Objective The aim of the study was to compare the phenotype/genotype relationships between FGD 1 and 2. Design and patients Forty patients with missense MC2R mutations and 22 patients with MRAP mutations were included. Forty-four of these patients had been referred for genetic screening and 18 were patients published by other authors. Results The median age at presentation for FGD type 1 was variable at 2·0 years; range 0·02–16 years, and this was associated with unusually tall stature, mean height SDS + 1·75 ± 1·53 (mean ± SD). In contrast, FGD type 2 presented at a much earlier median age (0·08 years; range at birth to 1·6 years) (P < 0·01) and patients were of normal height SDS + 0·12 ± 1·35 (P < 0·001). No differences in baseline cortisol or ACTH levels were seen between FGD types 1 and 2. Conclusion FGD type 2 appears to present earlier. This may reflect the functional significance of the underlying mutations in that all MRAP mutations are nonsense or splice site mutations that result in abolition of a functional protein, whereas most of the MC2R mutations are missense mutations and give rise to proteins with some residual function. Tall stature is associated with mutations in MC2R but not in MRAP. There were no other significant clinical distinctions between the two.
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            Pathophysiology of focal segmental glomerulosclerosis

            Focal segmental glomerulosclerosis (FSGS) is a major cause of idiopathic steroid-resistant nephrotic syndrome (SRNS) and end-stage kidney disease (ESKD). In recent years, animal models and studies of familial forms of nephrotic syndrome helped elucidate some mechanisms of podocyte injury and disease progression in FSGS. This article reviews some of the experimental and clinical data on the pathophysiology of FSGS.
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              Familial Glucocorticoid Deficiency: Advances in the Molecular Understanding of ACTH Action

              Familial glucocorticoid deficiency (FGD), otherwise known as hereditary unresponsiveness to ACTH, is a rare autosomal recessive disease characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Mutations of the ACTH receptor, also known as the melanocortin-2 receptor (MC2R), account for approximately 25% of FGD cases. More recently a second gene, MRAP (melanocortin-2 receptor accessory protein), was identified and found to account for a further 15–20%. MRAP encodes a small single transmembrane domain protein, which is essential in the trafficking of the MC2R to the cell surface. In this review, we will firstly summarize the clinical presentation and genetic aetiology of this condition. Secondly, we will discuss how the discovery of MRAP has enhanced our understanding of the mechanisms of ACTH/MC2R action. Finally, we will explore future developments in this field.
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                Author and article information

                Journal
                BMC Endocr Disord
                BMC Endocr Disord
                BMC Endocrine Disorders
                BioMed Central
                1472-6823
                2012
                11 December 2012
                : 12
                : 32
                Affiliations
                [1 ]Section of Endocrinology, Department of Medicine, Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi, 74800, Pakistan
                Article
                1472-6823-12-32
                10.1186/1472-6823-12-32
                3538046
                23232022
                75723501-45fe-4dae-8429-3b1d570a67bf
                Copyright ©2012 Ram et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 7 August 2012
                : 5 December 2012
                Categories
                Case Report

                Endocrinology & Diabetes
                familial glucocorticoid deficiency,familial focal segmental glomerulosclerosis,acth resistance

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