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      Three Novel AMHGene Mutations in a Patient with Persistent Müllerian Duct Syndrome and Normal AMH Serum Dosage

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          Abstract

          Background:Persistentmüllerian duct syndrome (PMDS) is characterized by the presence of uterus, fallopian tubes and the upper part of the vagina in 46,XY patients with perfectly virilized external genitalia. It is mostly caused by mutations of the AMH or AMH type 2 receptor (AMHR2) gene. The AMH serum level is very often low or undetectable in the AMH gene defect and normal in the AMHR2 gene defect. Aim: We investigate an Italian patient, genotypically and phenotypically male, observed at 1 month of age for a right inguinal hernia that at surgery showed the presence of both testes in the same hernial sac and uterus and fallopian tubes in the abdomen. Results: Genetic tests first showed the absence of the common 27-bp deletion in the AMHR2 gene, then the presence of three new sequence variations in the AMH geneleading to the following variants: the p.A405P carried by the paternal allele; the p.G326V plus the p.V508A carried by the maternal allele. Conclusions: The determination of serum AMH, performed after the genetic analysis, showed a normal level for age, suggesting that these mutations may affect the function and the bioactivity of the hormone and not the secretion rate.

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          Most cited references 11

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          Isolation of the bovine and human genes for müllerian inhibiting substance and expression of the human gene in animal cells

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            AMH and AMH receptor defects in persistent Müllerian duct syndrome.

            Anti-Müllerian hormone (AMH) produced by fetal Sertoli cells is responsible for regression of Müllerian ducts, the anlage for uterus and Fallopian tubes, during male sex differentiation. A member of the transforming growth factor-beta superfamily, AMH signals through two transmembrane receptors, type II which is specific and type I receptors, shared with the bone morphogenetic protein family. Mutations of the AMH and AMH receptor type II (AMHR-II) genes lead to persistence of the uterus and Fallopian tubes in males. Both conditions are transmitted according to a recessive autosomal pattern and are symptomatic only in males. Affected individuals are otherwise normally virilized, undergo normal male puberty; and may be fertile if testes, tightly attached to the Fallopian tubes, can be replaced in the scrotum. Approximately 85% of the cases are due, in similar proportions, to mutations of the AMH or AMHR-II gene. The genetic background does not influence the phenotype, the only difference is the level of circulating AMH which is normal for age in AMHR-II mutants and usually low or undetectable in AMH gene defects. This is due to lack of secretion, explained by the localization of the mutations in critical regions, based on the assumed 3D structure of the molecule. Similarly, lack of translocation to the surface membrane is responsible for the inactivity of AMHR-II molecules bearing mutations in the extracellular domain. In 15% of cases, the cause of the persistent Mullerian duct syndrome is unknown and could be related to complex malformations of the urogenital region, unrelated to AMH physiology.
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              Anti-müllerian hormone in early human development.

              Anti-müllerian hormone (AMH) is a glycoprotein produced by immature Sertoli cells and responsible for the regression of müllerian ducts in male fetuses. The ontogeny of the hormone in early human development was investigated. While no detectable AMH could be found in female fetal serum, in males, the mean +/- S.E.M. AMH serum concentration was 40.5 +/- 3.9 ng/ml from 19 to 30 weeks (n = 13), and 28.4 +/- 6.1 ng/ml from 30 weeks to term (n = 9). The latter value is significantly different from the mean AMH concentration in serum from boys aged 2 months to 2 years (43.1 +/- 3.7), suggesting that AMH production is sluggish during the perinatal period. The serum AMH concentration of a 46,XX male fetus was in the normal range for males. Using in situ hybridization, AMH transcripts were detected in the testicular tissue of all fetuses from 8 weeks onwards, but not in fetal ovaries nor in the yet undifferentiated gonadal tissue of a 7-week-old fetus bearing male-determining DNA sequences. Together, these data indicate that AMH is a reliable marker for the presence of functional testicular tissue and, as such, may be helpful for the diagnosis of fetal sex, particularly in the presence of sex chromosome abnormalities.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2008
                August 2008
                12 June 2008
                : 70
                : 2
                : 124-128
                Affiliations
                Department of Pediatrics, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, Italy
                Article
                137664 Horm Res 2008;70:124–128
                10.1159/000137664
                18547961
                © 2008 S. Karger AG, Basel

                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.

                Page count
                Figures: 2, References: 15, Pages: 5
                Categories
                Novel Insights from Clinical Practice

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