Ahmed

Bashamboo

Camats

Ferraz-de-Souza

Hughes

Idkowiak

Kyriakie Sarafoglou

Ledig

Pasterski

Pearlman

S. Faisal Ahmed

Sarafoglou

English

Crossref

The Journal of Clinical Endocrinology & Metabolism

Disorders of Sex Development: Challenges for the Future

Sarafoglou, Kyriakie

Ahmed, S. Faisal

Enlighten: Publications

Enlighten – Research publications by members of the University of Glasgow 
http://eprints.gla.ac.uk 
 
 
 
 
 
 
 
Sarafoglou, K., and Ahmed, S.F. (2012) Disorders of sex development: 
challenges for the future. Journal of Clinical Endocrinology and 
Metabolism, 97 (7). pp. 2292-2294. ISSN 0021-972X 
 
http://eprints.gla.ac.uk/70297 
 
Deposited on: 31 October 2012 
 
 
Disorders of Sex Development: Challenges for the
Future
Kyriakie Sarafoglou and S. Faisal Ahmed
Department of Pediatrics (K.S.), University of Minnesota Amplatz Children’s Hospital, Minneapolis,
Minnesota 55454; and Department of Child Health (S.F.A.), Royal Hospital for Sick Children, University
of Glasgow, Yorkhill, Glasgow G3 8SJ, United Kingdom
The perpetual challenge in the diagnosis and manage-ment of patients with disorders of sex development
(DSD), to paraphrase the adage, is that as our circle of
knowledge in the genetic mechanisms of DSD expands, so
does the circumference of darkness surrounding it. New
technologies (comparative genomic hybridization, se-
quencing by hybridization, and next generation sequenc-
ing) are rapidly generating massive amounts of informa-
tion on the pathogenesis of DSD (1). The caveat is that
identifying a pathogenic mutation may not predict the
clinical picture because phenotype can be highly variable,
even within the same family (2). Oligogenic modulators,
developmental switches, epigenetic influences, environ-
mental stimuli, and even imbalanced cis-regulation ofmu-
tant vs. wild-type alleles when mutations are present in a
heterozygous state may also be contributing factors to the
variable expression of phenotype (3).
A major step forward in organizing the molecular and
clinical information was the recent change in nomencla-
ture and classification of DSD. In 2006, the Pediatric En-
docrine Society (formerly known as the Lawson and
Wilkins Pediatric Endocrine Society) and the European
Society for Pediatric Endocrinology consensus group de-
finedDSD as congenital conditions in which development
of chromosomal, gonadal, or anatomical sex is atypical,
and broadly classified DSD into three groups based upon
cytogenetic, hormonal, gonadal histology, and clinical
findings: 46,XY DSD, 46,XXDSD, and sex chromosome
DSD (4). The classification reflected the natural history of
the diagnostic process in which the sex chromosomes are
the usual starting point for investigations of a child with
atypical genitalia. As our genetic and endocrine under-
standing of unclassified or syndromic conditions im-
proves, the DSD classification, which continues to gain
wide acceptance across the globe (5), has the flexibility to
incorporate them into its current structure. But there is still
a long way to go to where the genetic information can be
used to predict long-term outcomes to provide personal-
ized care for the DSD patient.
In some DSD, clinical diagnosis can be confirmed by
hormonal and molecular testing. For example, in com-
plete androgen insensitivity syndrome there is an 80–
90% chance that a 46,XY infant with normal female
genitalia and normal testosterone synthesis will have a
mutation in androgen receptor gene (6). Similarly, the
majority of 46,XX presenting with virilized genitalia
will have congenital adrenal hyperplasia with a muta-
tion in CYP21A2 where genotype-phenotype correla-
tions are excellent (7).
In cases of XY DSD with partially virilized genitalia,
a molecular diagnosis has been relatively elusive so that
diagnosis is guided by a thorough clinical, biochemical,
and anatomical evaluation of the affected infant. For
instance, only about 20% of these cases associated with
normal androgen synthesis will have a mutation in the
androgen receptor gene (6).
Discordance between molecular changes and func-
tional in vitro transactivation studies complicate even fur-
ther the efforts for attributing the particular DSD pheno-
type to the identified gene change. Furthermore, such
functional studies continue to remain in the realms of re-
search laboratories, and their large-scale clinical utility
remains unclear. The recent identification of mutations
associated with DSD in a poorly characterizedMAPK sig-
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2012-2178 Received May 9, 2012. Accepted May 16, 2012.
For article see page E1294
Abbreviation: DSD, Disorders of sex development.
S P E C I A L F E A T U R E
E d i t o r i a l
2292 jcem.endojournals.org J Clin Endocrinol Metab, July 2012, 97(7):2292–2294
naling pathway (8) suggests that theremay be a number of
other genes that may remain unidentified.
In this issue of the JCEM, the study by Camats et al. (9)
highlights the perpetual challenges that are faced by the
DSD classification as well as our understanding of the
genetic etiology of DSD. The investigators detected and
characterized 10 novel heterozygote NR5A1 mutations
froma groupof 10046,XYDSDand twoprimary ovarian
insufficiency patients from centers in Spain, Switzerland,
and Turkey. Through an international collaboration, the
authors found high variability in the clinical, biochemical,
histological, genetic, and functional characteristics of the
10 novelNR5A1mutations. Although the genotype-phe-
notype correlation remains elusive, the study adds to the
accumulating body of evidence that approximately 10%
of XY DSD patients will have a mutation in NR5A1 and
highlights the importance of collaborative efforts in build-
ing our knowledge base of DSD.
The Camats et al. study (9) also raises the issue that
some of the phenotypic variability may be a manifesta-
tion of time-dependent deterioration of gonadal tissue
and/or steroid secretion. This is an important phenom-
enon in DSD, where the manifestation of the gene mu-
tation may vary depending on the age of the patient, as
has been seen in other defects of testosterone synthesis
and/or metabolism caused by StAR, SRD5A2, or
CYP17A1 gene mutations.
To be able to take a critical step forward and begin
better utilization of the information provided in this and
other studies, careful collection of clinical data that de-
scribe the phenotype at diagnosis as well as at a later stage
remains a critical cornerstone for understanding etiology
and long-term outcome. For these rare conditions, these
data need to be serially collected in a standardizedmethod
and should ideally include a structured description of the
genitalia and gonads, the endocrine biochemistry, psycho-
logical and psychosocial development, and medical and
surgical therapeutic intervention.
However, to date the tools that have been available to
collect these data have been very variable, have lacked
uniformity, and have not been developed specifically for
DSD.The2006ConsensusWorkshoponDSDstressed the
need for creating and maintaining databases that can fa-
cilitate standardized collection of data that can cross-talk
across geographical boundaries and facilitate interna-
tional collaboration (5). An international web-based reg-
istry, the I-DSD Registry (www.i-dsd.org), has now been
in operation for over 4 yr and has encouraged the devel-
opment ofmulticenter projects as well as the development
of other registries (10). It is now important that these reg-
istries continue to collect standardized uniform data so
that they can cross-talk in the future. In addition to re-
search, these registries have the potential to act as a patient
management tool and can also facilitate the development
of a professional and patient network.
The need for collecting standardized information
and involving the clinician in this exercise is now much
greater as the output from genetic analysis increases.
Because increasing numbers of people with syndromal
DSD are undergoing analysis using array comparative
genomic hybridization and next generation sequencing,
more pathogenic rearrangements are being reported,
and whereas they may reveal unique insights into the
mechanism of gonadal development, they may also
highlight the involvement of other coexisting disease
(1). In patients with disorders of gonadal development,
small deletions or duplications that are likely to be caus-
ative of the condition can be found in 25% of cases where
other organ systems are affected, whereas they are only
found in 6% of cases where only testis development was
affected (11). With the reducing costs of next generation
sequencing, exomeandcomplete genome sequencingoffer
much richer possibilities for understanding disease. Nev-
ertheless, the introduction of expanded genetic testing is
not without its own risk, and there is a need to develop a
clinical infrastructure that can cope with the increased
level of genetic information that will be available in the
future.The clinical validity and relevanceof the results can
only be judged after thorough evaluation of the clinical
features of the case. Recent guidance issued in the United
Kingdom has also called for greater involvement of the
clinical geneticist in themanagementof this information in
a multidisciplinary clinical setting (12). In addition to
complex genetic analysis, recent technological advances in
the field of steroid analysiswill lead to the identification of
new enzymatic causes ofDSD (13).However, this analysis
will also yield a large amount of information that will
require bioinformatic analysis. These specialist techniques
shall only be available in a handful of centers and thus
require the clinical and scientific community to increase
their ability to work as a network.
Finally, future research initiatives should incorporate a
move toward a greater understanding of how genetic
knowledge in DSD affects the quality of life of the patient
and the family. It is generally believed that the knowledge
of a genetic cause of DSD helps with explaining the con-
dition to the family and may help with genetic counseling
and discussing future risks. Although this may be clear
from the point of view of a condition such as congenital
adrenal hyperplasia, there is little published evidence that
the possession of genetic data in cases of XY DSD char-
acterized by partial virilization alters the long-term qual-
ity-of-life outcomes.
J Clin Endocrinol Metab, July 2012, 97(7):2292–2294 jcem.endojournals.org 2293
Acknowledgments
Address all correspondence and requests for reprints to:Kyriakie
Sarafoglou, M.D., University of Minnesota Amplatz Children’s
Hospital, Department of Pediatrics, Division of Pediatric Endo-
crinology, Division of Genetics and Metabolism, East Building,
Room MB671, 2450 Riverside Avenue, Minneapolis, Minne-
sota 55454. E-mail: saraf010@umn.edu.
S.F.A.was funded inpart byEuroDSD(in theEuropeanCom-
munity’s Seventh Framework Programme FP7/2007–2013 un-
der grant agreement no. 201444) and is currently supported by
a partnership grant from the Medical Research Council of the
United Kingdom (G1100236).
Disclosure Summary: The authors have nothing to disclose.
References
1. Bashamboo A, Ledig S, Wieacker P, Achermann JC, Achermann J,
McElreaveyK 2010New technologies for the identification of novel
genetic markers of disorders of sex development (DSD). Sex Dev
4:213–224
2. Sarafoglou K, Ostrer H 2000 Clinical review 111: familial sex re-
versal: a review. J Clin Endocrinol Metab 85:483–493
3. Ferraz-de-Souza B, Lin L, Achermann JC 2011 Steroidogenic fac-
tor-1 (SF-1, NR5A1) and human disease. Mol Cell Endocrinol 336:
198–205
4. Hughes IA, Houk C, Ahmed SF, Lee PA 2006 Consensus statement
on management of intersex disorders. Arch Dis Child 91:554–563
5. Pasterski V, Prentice P, Hughes IA 2010 Impact of the consensus
statement and thenewDSDclassification system.Best PractResClin
Endocrinol Metab 24:187–195
6. Ahmed SF, Cheng A, Dovey L, Hawkins JR, Martin H, Rowland J,
Shimura N, Tait AD, Hughes IA 2000 Phenotypic features, andro-
gen receptor binding, and mutational analysis in 278 clinical cases
reported as androgen insensitivity syndrome. J Clin Endocrinol
Metab 85:658–665
7. Sarafoglou K, Lorentz C, Otten N, OettingW, Grebe S 3 June 2011
Molecular testing in congenital adrenal hyperplasia due to 21-
hydroxylase deficiency in the era of newborn screening. Clin Genet
doi: 10.1111/j.1399-0004.2011.01694.x
8. Pearlman A, Loke J, Le Caignec C, White S, Chin L, Friedman A,
Warr N, Willan J, Brauer D, Farmer C, Brooks E, Oddoux C, Riley
B, Shajahan S, Camerino G, Homfray T, Crosby AH, Couper J,
David A, Greenfield A, Sinclair A, Ostrer H 2010 Mutations in
MAP3K1 cause 46,XY disorders of sex development and implicate
a common signal transduction pathway in human testis determina-
tion. Am J Hum Genet 87:898–904
9. CamatsN, Pandey AV, Ferna´ndez-CancioM,Andaluz P, JannerM,
Tora´n N, Moreno F, Bereket A, Akcay T, García-García E, Mun˜oz
MT, Gracia R, NistalM, Castan˜o L,Mullis PE, Carrascosa A, Audí
L, Flu¨ck CE 2012 Ten novel mutations in the NR5A1 gene cause
disordered sex development in 46,XY and ovarian insufficiency in
46,XX individuals. J Clin Endocrinol Metab 97:E1294–E1306
10. Ahmed SF, Rodie M, Jiang J, Sinnott RO 2010 The European dis-
order of sex development registry: a virtual research environment.
Sex Dev 4:192–198
11. Ledig S, Hiort O, Scherer G, Hoffmann M, Wolff G, Morlot S,
Kuechler A, Wieacker P 2010 Array-CGH analysis in patients with
syndromic and non-syndromic XY gonadal dysgenesis: evaluation
of array CGH as diagnostic tool and search for new candidate loci.
Hum Reprod 25:2637–2646
12. Ahmed SF, Achermann JC, Arlt W, Balen A, Conway G, Edwards
Z, Elford S, Hughes IA, Izatt L, KroneN,Miles H, O’Toole S, Perry
L, SandersC, SimmondsM,WallaceAM,WattA,WillisD2011UK
guidance on the initial evaluation of an infant or an adolescent with
a suspected disorder of sex development. Clin Endocrinol (Oxf)
75:12–26
13. Idkowiak J, Lavery GG, Dhir V, Barrett TG, Stewart PM, Krone N,
Arlt W 2011 Premature adrenarche: novel lessons from early onset
androgen excess. Eur J Endocrinol 165:189–207
2294 Sarafoglou and Ahmed DSD: Challenges for the Future J Clin Endocrinol Metab, July 2012, 97(7):2292–2294


Disorders of sex development: challenges for the future

Enlighten

Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk        Sarafoglou, K., and Ahmed, S.F. (2012) Disorders of sex development: challenges for the future. Journal of Clinical Endocrinology and Metabolism, 97 (7). pp. 2292-2294. ISSN 0021-972X  http://eprints.gla.ac.uk/70297  Deposited on: 31 October 2012   Disorders of Sex Development: Challenges for theFutureKyriakie Sarafoglou and S. Faisal AhmedDepartment of Pediatrics (K.S.), University of Minnesota Amplatz Children’s Hospital, Minneapolis,Minnesota 55454; and Department of Child Health (S.F.A.), Royal Hospital for Sick Children, Universityof Glasgow, Yorkhill, Glasgow G3 8SJ, United KingdomThe perpetual challenge in the diagnosis and manage-ment of patients with disorders of sex development(DSD), to paraphrase the adage, is that as our circle ofknowledge in the genetic mechanisms of DSD expands, sodoes the circumference of darkness surrounding it. Newtechnologies (comparative genomic hybridization, se-quencing by hybridization, and next generation sequenc-ing) are rapidly generating massive amounts of informa-tion on the pathogenesis of DSD (1). The caveat is thatidentifying a pathogenic mutation may not predict theclinical picture because phenotype can be highly variable,even within the same family (2). Oligogenic modulators,developmental switches, epigenetic influences, environ-mental stimuli, and even imbalanced cis-regulation ofmu-tant vs. wild-type alleles when mutations are present in aheterozygous state may also be contributing factors to thevariable expression of phenotype (3).A major step forward in organizing the molecular andclinical information was the recent change in nomencla-ture and classification of DSD. In 2006, the Pediatric En-docrine Society (formerly known as the Lawson andWilkins Pediatric Endocrine Society) and the EuropeanSociety for Pediatric Endocrinology consensus group de-finedDSD as congenital conditions in which developmentof chromosomal, gonadal, or anatomical sex is atypical,and broadly classified DSD into three groups based uponcytogenetic, hormonal, gonadal histology, and clinicalfindings: 46,XY DSD, 46,XXDSD, and sex chromosomeDSD (4). The classification reflected the natural history ofthe diagnostic process in which the sex chromosomes arethe usual starting point for investigations of a child withatypical genitalia. As our genetic and endocrine under-standing of unclassified or syndromic conditions im-proves, the DSD classification, which continues to gainwide acceptance across the globe (5), has the flexibility toincorporate them into its current structure. But there is stilla long way to go to where the genetic information can beused to predict long-term outcomes to provide personal-ized care for the DSD patient.In some DSD, clinical diagnosis can be confirmed byhormonal and molecular testing. For example, in com-plete androgen insensitivity syndrome there is an 80–90% chance that a 46,XY infant with normal femalegenitalia and normal testosterone synthesis will have amutation in androgen receptor gene (6). Similarly, themajority of 46,XX presenting with virilized genitaliawill have congenital adrenal hyperplasia with a muta-tion in CYP21A2 where genotype-phenotype correla-tions are excellent (7).In cases of XY DSD with partially virilized genitalia,a molecular diagnosis has been relatively elusive so thatdiagnosis is guided by a thorough clinical, biochemical,and anatomical evaluation of the affected infant. Forinstance, only about 20% of these cases associated withnormal androgen synthesis will have a mutation in theandrogen receptor gene (6).Discordance between molecular changes and func-tional in vitro transactivation studies complicate even fur-ther the efforts for attributing the particular DSD pheno-type to the identified gene change. Furthermore, suchfunctional studies continue to remain in the realms of re-search laboratories, and their large-scale clinical utilityremains unclear. The recent identification of mutationsassociated with DSD in a poorly characterizedMAPK sig-ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2012 by The Endocrine Societydoi: 10.1210/jc.2012-2178 Received May 9, 2012. Accepted May 16, 2012.For article see page E1294Abbreviation: DSD, Disorders of sex development.S P E C I A L F E A T U R EE d i t o r i a l2292 jcem.endojournals.org J Clin Endocrinol Metab, July 2012, 97(7):2292–2294naling pathway (8) suggests that theremay be a number ofother genes that may remain unidentified.In this issue of the JCEM, the study by Camats et al. (9)highlights the perpetual challenges that are faced by theDSD classification as well as our understanding of thegenetic etiology of DSD. The investigators detected andcharacterized 10 novel heterozygote NR5A1 mutationsfroma groupof 10046,XYDSDand twoprimary ovarianinsufficiency patients from centers in Spain, Switzerland,and Turkey. Through an international collaboration, theauthors found high variability in the clinical, biochemical,histological, genetic, and functional characteristics of the10 novelNR5A1mutations. Although the genotype-phe-notype correlation remains elusive, the study adds to theaccumulating body of evidence that approximately 10%of XY DSD patients will have a mutation in NR5A1 andhighlights the importance of collaborative efforts in build-ing our knowledge base of DSD.The Camats et al. study (9) also raises the issue thatsome of the phenotypic variability may be a manifesta-tion of time-dependent deterioration of gonadal tissueand/or steroid secretion. This is an important phenom-enon in DSD, where the manifestation of the gene mu-tation may vary depending on the age of the patient, ashas been seen in other defects of testosterone synthesisand/or metabolism caused by StAR, SRD5A2, orCYP17A1 gene mutations.To be able to take a critical step forward and beginbetter utilization of the information provided in this andother studies, careful collection of clinical data that de-scribe the phenotype at diagnosis as well as at a later stageremains a critical cornerstone for understanding etiologyand long-term outcome. For these rare conditions, thesedata need to be serially collected in a standardizedmethodand should ideally include a structured description of thegenitalia and gonads, the endocrine biochemistry, psycho-logical and psychosocial development, and medical andsurgical therapeutic intervention.However, to date the tools that have been available tocollect these data have been very variable, have lackeduniformity, and have not been developed specifically forDSD.The2006ConsensusWorkshoponDSDstressed theneed for creating and maintaining databases that can fa-cilitate standardized collection of data that can cross-talkacross geographical boundaries and facilitate interna-tional collaboration (5). An international web-based reg-istry, the I-DSD Registry (www.i-dsd.org), has now beenin operation for over 4 yr and has encouraged the devel-opment ofmulticenter projects as well as the developmentof other registries (10). It is now important that these reg-istries continue to collect standardized uniform data sothat they can cross-talk in the future. In addition to re-search, these registries have the potential to act as a patientmanagement tool and can also facilitate the developmentof a professional and patient network.The need for collecting standardized informationand involving the clinician in this exercise is now muchgreater as the output from genetic analysis increases.Because increasing numbers of people with syndromalDSD are undergoing analysis using array comparativegenomic hybridization and next generation sequencing,more pathogenic rearrangements are being reported,and whereas they may reveal unique insights into themechanism of gonadal development, they may alsohighlight the involvement of other coexisting disease(1). In patients with disorders of gonadal development,small deletions or duplications that are likely to be caus-ative of the condition can be found in 25% of cases whereother organ systems are affected, whereas they are onlyfound in 6% of cases where only testis development wasaffected (11). With the reducing costs of next generationsequencing, exomeandcomplete genome sequencingoffermuch richer possibilities for understanding disease. Nev-ertheless, the introduction of expanded genetic testing isnot without its own risk, and there is a need to develop aclinical infrastructure that can cope with the increasedlevel of genetic information that will be available in thefuture.The clinical validity and relevanceof the results canonly be judged after thorough evaluation of the clinicalfeatures of the case. Recent guidance issued in the UnitedKingdom has also called for greater involvement of theclinical geneticist in themanagementof this information ina multidisciplinary clinical setting (12). In addition tocomplex genetic analysis, recent technological advances inthe field of steroid analysiswill lead to the identification ofnew enzymatic causes ofDSD (13).However, this analysiswill also yield a large amount of information that willrequire bioinformatic analysis. These specialist techniquesshall only be available in a handful of centers and thusrequire the clinical and scientific community to increasetheir ability to work as a network.Finally, future research initiatives should incorporate amove toward a greater understanding of how geneticknowledge in DSD affects the quality of life of the patientand the family. It is generally believed that the knowledgeof a genetic cause of DSD helps with explaining the con-dition to the family and may help with genetic counselingand discussing future risks. Although this may be clearfrom the point of view of a condition such as congenitaladrenal hyperplasia, there is little published evidence thatthe possession of genetic data in cases of XY DSD char-acterized by partial virilization alters the long-term qual-ity-of-life outcomes.J Clin Endocrinol Metab, July 2012, 97(7):2292–2294 jcem.endojournals.org 2293AcknowledgmentsAddress all correspondence and requests for reprints to:KyriakieSarafoglou, M.D., University of Minnesota Amplatz Children’sHospital, Department of Pediatrics, Division of Pediatric Endo-crinology, Division of Genetics and Metabolism, East Building,Room MB671, 2450 Riverside Avenue, Minneapolis, Minne-sota 55454. E-mail: saraf010@umn.edu.S.F.A.was funded inpart byEuroDSD(in theEuropeanCom-munity’s Seventh Framework Programme FP7/2007–2013 un-der grant agreement no. 201444) and is currently supported bya partnership grant from the Medical Research Council of theUnited Kingdom (G1100236).Disclosure Summary: The authors have nothing to disclose.References1. Bashamboo A, Ledig S, Wieacker P, Achermann JC, Achermann J,McElreaveyK 2010New technologies for the identification of novelgenetic markers of disorders of sex development (DSD). Sex Dev4:213–2242. Sarafoglou K, Ostrer H 2000 Clinical review 111: familial sex re-versal: a review. J Clin Endocrinol Metab 85:483–4933. Ferraz-de-Souza B, Lin L, Achermann JC 2011 Steroidogenic fac-tor-1 (SF-1, NR5A1) and human disease. Mol Cell Endocrinol 336:198–2054. Hughes IA, Houk C, Ahmed SF, Lee PA 2006 Consensus statementon management of intersex disorders. Arch Dis Child 91:554–5635. Pasterski V, Prentice P, Hughes IA 2010 Impact of the consensusstatement and thenewDSDclassification system.Best PractResClinEndocrinol Metab 24:187–1956. Ahmed SF, Cheng A, Dovey L, Hawkins JR, Martin H, Rowland J,Shimura N, Tait AD, Hughes IA 2000 Phenotypic features, andro-gen receptor binding, and mutational analysis in 278 clinical casesreported as androgen insensitivity syndrome. J Clin EndocrinolMetab 85:658–6657. Sarafoglou K, Lorentz C, Otten N, OettingW, Grebe S 3 June 2011Molecular testing in congenital adrenal hyperplasia due to 21-hydroxylase deficiency in the era of newborn screening. Clin Genetdoi: 10.1111/j.1399-0004.2011.01694.x8. Pearlman A, Loke J, Le Caignec C, White S, Chin L, Friedman A,Warr N, Willan J, Brauer D, Farmer C, Brooks E, Oddoux C, RileyB, Shajahan S, Camerino G, Homfray T, Crosby AH, Couper J,David A, Greenfield A, Sinclair A, Ostrer H 2010 Mutations inMAP3K1 cause 46,XY disorders of sex development and implicatea common signal transduction pathway in human testis determina-tion. Am J Hum Genet 87:898–9049. CamatsN, Pandey AV, Ferna´ndez-CancioM,Andaluz P, JannerM,Tora´n N, Moreno F, Bereket A, Akcay T, García-García E, Mun˜ozMT, Gracia R, NistalM, Castan˜o L,Mullis PE, Carrascosa A, AudíL, Flu¨ck CE 2012 Ten novel mutations in the NR5A1 gene causedisordered sex development in 46,XY and ovarian insufficiency in46,XX individuals. J Clin Endocrinol Metab 97:E1294–E130610. Ahmed SF, Rodie M, Jiang J, Sinnott RO 2010 The European dis-order of sex development registry: a virtual research environment.Sex Dev 4:192–19811. Ledig S, Hiort O, Scherer G, Hoffmann M, Wolff G, Morlot S,Kuechler A, Wieacker P 2010 Array-CGH analysis in patients withsyndromic and non-syndromic XY gonadal dysgenesis: evaluationof array CGH as diagnostic tool and search for new candidate loci.Hum Reprod 25:2637–264612. Ahmed SF, Achermann JC, Arlt W, Balen A, Conway G, EdwardsZ, Elford S, Hughes IA, Izatt L, KroneN,Miles H, O’Toole S, PerryL, SandersC, SimmondsM,WallaceAM,WattA,WillisD2011UKguidance on the initial evaluation of an infant or an adolescent witha suspected disorder of sex development. Clin Endocrinol (Oxf)75:12–2613. Idkowiak J, Lavery GG, Dhir V, Barrett TG, Stewart PM, Krone N,Arlt W 2011 Premature adrenarche: novel lessons from early onsetandrogen excess. Eur J Endocrinol 165:189–2072294 Sarafoglou and Ahmed DSD: Challenges for the Future J Clin Endocrinol Metab, July 2012, 97(7):2292–2294

Array-CGH analysis in patients with syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci. Hum Reprod

Clinical review 111: familial sex reversal: a review.

Consensus statement on management of intersex disorders.

disorders of sex development and implicate a common signal transduction pathway in human testis determination.

Edwards Z,ElfordS,HughesIA,IzattL,KroneN,MilesH,O’TooleS,Perry L,SandersC,SimmondsM,WallaceAM,WattA,WillisD2011UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development. Clin Endocrinol (Oxf)

gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals.

McElreaveyK2010Newtechnologiesfortheidentificationofnovel genetic markers of disorders of sex development (DSD). Sex Dev 4:213–224

Molecular testing in congenital adrenal hyperplasia due to 21-hydroxylase deficiency in the era of newborn screening.

Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome.

Premature adrenarche: novel lessons from early onset androgen excess.

Steroidogenic factor-1 (SF-1, NR5A1) and human disease.

The European disorder of sex development registry: a virtual research environment.

http://eprints.gla.ac.uk/70297/1/70297.pdf

Disorders of sex development: challenges for the future

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