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      Gonadotropin-Dependent Precocious Puberty in a Patient with X-Linked Adrenal Hypoplasia Congenita Caused by a Novel DAX-1 Mutation

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          Abstract

          Background/Aims: X-linked adrenal hypoplasia congenita (AHC) is typically characterized by a DAX-1 gene mutation and hypogonadotropic hypogonadism. However, rare cases with precocious puberty or normal puberty have been reported. Currently, the mechanism of action of the DAX-1 gene on puberty is not clearly known. Case Report: We report a male who was diagnosed as having AHC in the newborn period and detected as having stop codon Q155 X mutation in the DAX-1 gene. This subject developed central precocious puberty when he was 9 months old. Results: This paper is the first case report of AHC, central precocious puberty and a mutation in the DAX-1 gene. DAX-1 gene mutations can result in various phenotypes. Conclusion: In cases with AHC, central precocious puberty can develop rather than hypogonadotropic hypogonadism, which is the most frequently observed puberty disorder related to DAX-1 gene mutations.

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          Phenotypic spectrum of mutations in DAX-1 and SF-1.

          John Achermann, Joshua J Meeks, J. Larry Jameson (2001)
          SF-1 (steroidogenic factor-1) (NR5A1) and DAX-1 (dosage-sensitive sex-reversal, adrenal hypoplasia congenital, X chromosome) (NR0B1) are orphan nuclear receptors that are expressed in the adrenal gland, gonads, ventromedial hypothalamus (VMH), and pituitary gonadotrope cells. The function of these genes has been clarified by examining the consequences of naturally occurring mutations in humans, as well as targeted disruption of the genes in mice. Mutations in DAX1 cause adrenal hypoplasia congenita (AHC), an X-linked disorder characterized by adrenal insufficiency and failure to undergo puberty because of hypogonadotropic hypogonadism. Most DAX1 mutations introduce frameshifts and/or cause premature termination of the protein. Relatively few missense mutations have been described and all are located within the carboxy-terminal half of the protein. Transfection assays demonstrate that AHC-associated DAX1 mutations abrogate its ability to act as a transcriptional repressor of SF-1. Most boys affected with AHC present with adrenal insufficiency in early infancy, although a significant fraction present in later childhood or even as young adults. The degree of gonadotropin deficiency is also variable. With the exception of one mild missense DAX1 mutation, genotype-phenotype correlations have been elusive, suggesting an important role for modifier genes. Targeted mutagenesis of Dax1 (Ahch) in mice reveals an additional role in testis development and spermatogenesis. Similar abnormalities appear to be present in humans. Targeted mutagenesis of Sf1 (FtzF1) prevents gonadal and adrenal development, and causes male-to-female sex-reversal. A human XY individual with a heterozygous SF1 mutation presented with adrenal insufficiency and complete sex-reversal; this DNA-binding domain mutation prevents SF-1 stimulation of its target genes. In addition to their clinical relevance, studies of SF1 and DAX1 are proving useful for unraveling the genetic pathways that govern adrenal and gonadal development.
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            A Case of X-Linked Adrenal Hypoplasia Congenita, Central Precocious Puberty and Absence of the DAX-1 Gene: Implications for Pubertal Regulation

            Kah-Yin Loke, Larry Poh, Warren Wei Rhen Lee … (2009)
            Background/Aims: X-linked adrenal hypoplasia congenita (AHC) is typically associated with DAX-1 mutations and hypogonadotropic hypogonadism. However, atypical cases of X-linked AHC in association with central precocious puberty and even normal puberty have rarely been reported, although the mechanism of action remains unknown. Case Report: This is a case report of a boy with X-linked AHC associated with Duchenne muscular dystrophy, whose clinical presentation led to analysis of the DAX-1 , glycerol kinase ( GK1) and dystrophin genes, which were amplified by polymerase chain reaction, with Southern blot analysis of the AHC locus. Results: There was a non-contiguous deletion of the DAX-1 and GK1 genes, with deletion of the dystrophingene from exons 3 to 79. Conclusion: This is the first report of X-linked AHC, central precocious puberty in the absence of the DAX-1 gene. The fact that a ‘loss of function’ DAX-1 mutation can be associated with hypogonadotropic hypogonadism, precocious and normal puberty, suggests that DAX-1 is but one of several transcription factors which regulate puberty, and provides further evidence that other transcription factors may interact with DAX-1 and influence gonadal regulation in a complex, but hierarchical fashion.
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              A Novel Missense Mutation in Dax-1 with an Unusual Presentation of X-Linked Adrenal Hypoplasia Congenita

              Imran Ahmad, Wendy Paterson, Lin Lin … (2007)
              A male presented at age 2.2 years with a 6-week history of intermittent vomiting and hyperpigmentation. Investigations showed salt wasting with hyperkalaemia, a grossly impaired cortisol response to ACTH stimulation, elevated renin and ACTH. Family history revealed that two maternal uncles had died soon after birth. A third uncle failed to thrive during infancy but improved with a course of cortisone, then being untreated until further investigation revealed adrenal insufficiency. A fourth uncle died aged 10 days, with urinary salt loss and hypoplastic adrenal glands at postmortem. Molecular studies on the proband, his mother, maternal grandmother, and surviving uncle showed a novel C to G substitution at nucleotide position 794 (missense mutation T265R) in the DAX1 (NR0B1) gene. The proband has responded well to steroid replacement but has proved sensitive to 9α-fludrocortisone treatment, developing hypertension on a dose of 133 µg/m 2 /day. At 8.8 years he was noted to have testicular volumes of 4 ml, despite no other evidence of secondary sexual development and prepubertal gonadotrophin levels. Novel features of this family include a novel DAX1 mutation, marked variability in age of presentation, hypertension on ‘standard’ doses of 9α-fludrocortisone and mild testicular enlargement.
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                Author and article information

                Journal
                Journal ID (publisher-id): HRP
                Journal ID (nlm-ta): Horm Res Paediatr
                Journal ID (doi): 10.1159/issn.1663-2818
                Title: Hormone Research in Paediatrics
                Publisher: S. Karger AG
                ISSN (Print): 1663-2818
                ISSN (Electronic): 1663-2826
                Publication date Subscription-year: 2011
                Publication date (Print): February 2011
                Publication date (Electronic): 22 October 2010
                Volume: 75
                Issue: 2
                Pages: 153-156
                Affiliations
                aDepartment of Pediatric Endocrinology and Metabolism, and bDepartment of Clinical Genetics, Ege University, Izmir, Turkey; cInstitut de Pharmacologie Moléculaire et Cellulaire CNRS, Université de Nice Sophia Antipolis, Valbonne, France
                Author notes
                *Samim Ozen, MD, Department of Pediatric Endocrinology and Metabolism, Ege University School of Medicine, TR–35100 Izmir (Turkey), Tel. +90 232 390 1230, Fax +90 232 388 6366, E-Mail samimozen@gmail.com
                Article
                Publisher ID: 320701 Other ID: Horm Res Paediatr 2011;75:153–156
                DOI: 10.1159/000320701
                PubMed ID: 20975255
                SO-VID: bdf2c535-f41d-454f-a83d-69bb40f55ace
                Copyright © © 2010 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 25 June 2010
                Date accepted : 26 August 2010
                Page count
                Tables: 1, Pages: 4
                Categories
                Subject: Novel Insights from Clinical Practice

                ScienceOpen disciplines: Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Keywords: Central precocious puberty,X-linked adrenal hypoplasia congenita,DAX-1 gene mutation
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes, Neurology, Nutrition & Dietetics, Sexual medicine, Internal medicine, Pharmacology & Pharmaceutical medicine
                Keywords: Central precocious puberty, X-linked adrenal hypoplasia congenita, DAX-1 gene mutation

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