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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Etiological Classification and Clinical Assessment of Children and
Adolescents with Disorders of Sex Development</title><author><name sortKey="Erdo An, Sema" sort="Erdo An, Sema" uniqKey="Erdo An S" first="Sema" last="Erdo An">Sema Erdo An</name><affiliation><nlm:aff id="A1"> Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey</nlm:aff></affiliation></author><author><name sortKey="Kara, Cengiz" sort="Kara, Cengiz" uniqKey="Kara C" first="Cengiz" last="Kara">Cengiz Kara</name><affiliation><nlm:aff id="A1"> Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey</nlm:aff></affiliation></author><author><name sortKey="Ucakturk, Ahmet" sort="Ucakturk, Ahmet" uniqKey="Ucakturk A" first="Ahmet" last="Uçaktürk">Ahmet Uçaktürk</name><affiliation><nlm:aff id="A1"> Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey</nlm:aff></affiliation></author><author><name sortKey="Ayd N, Murat" sort="Ayd N, Murat" uniqKey="Ayd N M" first="Murat" last="Ayd N">Murat Ayd N</name><affiliation><nlm:aff id="A1"> Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21750636</idno><idno type="pmc">3119445</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119445</idno><idno type="RBID">PMC:3119445</idno><idno type="doi">10.4274/jcrpe.v3i2.16</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">004048</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004048</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Etiological Classification and Clinical Assessment of Children and
Adolescents with Disorders of Sex Development</title><author><name sortKey="Erdo An, Sema" sort="Erdo An, Sema" uniqKey="Erdo An S" first="Sema" last="Erdo An">Sema Erdo An</name><affiliation><nlm:aff id="A1"> Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey</nlm:aff></affiliation></author><author><name sortKey="Kara, Cengiz" sort="Kara, Cengiz" uniqKey="Kara C" first="Cengiz" last="Kara">Cengiz Kara</name><affiliation><nlm:aff id="A1"> Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey</nlm:aff></affiliation></author><author><name sortKey="Ucakturk, Ahmet" sort="Ucakturk, Ahmet" uniqKey="Ucakturk A" first="Ahmet" last="Uçaktürk">Ahmet Uçaktürk</name><affiliation><nlm:aff id="A1"> Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey</nlm:aff></affiliation></author><author><name sortKey="Ayd N, Murat" sort="Ayd N, Murat" uniqKey="Ayd N M" first="Murat" last="Ayd N">Murat Ayd N</name><affiliation><nlm:aff id="A1"> Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Clinical Research in Pediatric Endocrinology</title><idno type="ISSN">1308-5727</idno><idno type="eISSN">1308-5735</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><bold>Objective:</bold> In 2006, the Lawson Wilkins Pediatric Endocrine Society
(LWPES) and the European Society for Paediatric Endocrinology (ESPE) published a
consensus statement on management of intersex disorders. The aim of our study
was to determine the etiological distribution of disorders of sex development
(DSD) according to the new DSD classification system and to evaluate the
clinical features of DSDs in our patient cohort. </p><p><bold>Methods:</bold> We retrospectively reviewed the records of patients
followed up during the past three years. The subjects were divided into three
etiologic groups according to their karyotypes. The definite diagnosesin each
subgroup were established by clinical and laboratory investigations including
abdominopelvic imaging as well as basal and stimulated hormone measurements.
Molecular genetic testing, except for CYP21A2 gene, could not be performed. </p><p><bold>Results:</bold> Out of a total of 95 patients, 26 had sex chromosome DSD,
45 had 46,XY DSD and 24 had 46,XX DSD. The most common causes of DSDs were
Turner’s syndrome (TS), congenital adrenal hyperplasia (CAH) and androgen
insensitivity syndrome (AIS). There was a wide variation in age of presentation
ranging from 1 day to 17.5 years with a mean of 6.5±6.5 years. The most
frequent complaints at presentation were ambiguous genitalia, isolated perineal
hypospadias and short stature. </p><p><bold>Conclusion:</bold> The results of our study demonstrate that the new DSD
classification system leads to a major change in the distribution of etiological
diagnoses of DSDs, which is exemplified by the significant frequencies of TS and
vanishing testes syndrome. This alteration expands the clinical spectrum and
increases the mean age at diagnosis. However, the most common causes of
ambiguous genitalia, such as CAH and AIS, remain unchanged. Further studies
using molecular genetic analyses are needed to give a more precise distribution
of etiologies of DSDs, especially in 46,XY patients.</p><p><bold>Conflict of interest:</bold>None declared.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hughes, Ia" uniqKey="Hughes I">IA Hughes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Pa" uniqKey="Lee P">PA Lee</name></author><author><name sortKey="Houk, Cp" uniqKey="Houk C">CP Houk</name></author><author><name sortKey="Ahmed, Sf" uniqKey="Ahmed S">SF Ahmed</name></author><author><name sortKey="Hughes, Ia" uniqKey="Hughes I">IA Hughes</name></author><author><name sortKey="International Consensus Conference On Intersex Organized By The X0a X09 X09 X09 X09 X09 X09 X09 X09 Lawson Wilkins Pediatric Endocrine Society And The European Society X0a X09 X09 X09 X09 X09 X09 X09 X09 For Paediatric, Endocrinology" uniqKey="International Consensus Conference On Intersex Organized By The X0a X09 X09 X09 X09 X09 X09 X09 X09 Lawson Wilkins Pediatric Endocrine Society And The European Society X0a X09 X09 X09 X09 X09 X09 X09 X09 For Paediatric E">Endocrinology. International Consensus Conference on Intersex organized by the
Lawson Wilkins Pediatric Endocrine Society and the European Society
for Paediatric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Pa" uniqKey="Lee P">PA Lee</name></author><author><name sortKey="Houk, Cp" uniqKey="Houk C">CP Houk</name></author><author><name sortKey="Ahmed, Sf" uniqKey="Ahmed S">SF Ahmed</name></author><author><name sortKey="Hughes, Ia" uniqKey="Hughes I">IA Hughes</name></author><author><name sortKey="International Consensus Conference On Intersex Organized By The X0a X09 X09 X09 X09 X09 X09 X09 X09 Lawson Wilkins Pediatric Endocrine Society And The European Society X0a X09 X09 X09 X09 X09 X09 X09 X09 For Paediatric, Endocrinology" uniqKey="International Consensus Conference On Intersex Organized By The X0a X09 X09 X09 X09 X09 X09 X09 X09 Lawson Wilkins Pediatric Endocrine Society And The European Society X0a X09 X09 X09 X09 X09 X09 X09 X09 For Paediatric E">Endocrinology International Consensus Conference on Intersex organized by the
Lawson Wilkins Pediatric Endocrine Society and the European Society
for Paediatric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carillo, Aa" uniqKey="Carillo A">AA Carillo</name></author><author><name sortKey="Berkowitz, Gd" uniqKey="Berkowitz G">GD Berkowitz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rapaport, R" uniqKey="Rapaport R">R Rapaport</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prader, A" uniqKey="Prader A">A. Prader</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ahmed, Sf" uniqKey="Ahmed S">SF Ahmed</name></author><author><name sortKey="Khwaja, O" uniqKey="Khwaja O">O Khwaja</name></author><author><name sortKey="Hughes, Ia" uniqKey="Hughes I">IA Hughes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kubini, K" uniqKey="Kubini K">K Kubini</name></author><author><name sortKey="Zachmann, M" uniqKey="Zachmann M">M Zachmann</name></author><author><name sortKey="Albers, N" uniqKey="Albers N">N Albers</name></author><author><name sortKey="Hiort, O" uniqKey="Hiort O">O Hiort</name></author><author><name sortKey="Bettendorf, M" uniqKey="Bettendorf M">M Bettendorf</name></author><author><name sortKey="Wolfle, J" uniqKey="Wolfle J">J Wölfle</name></author><author><name sortKey="Bidlingmaier, F" uniqKey="Bidlingmaier F">F Bidlingmaier</name></author><author><name sortKey="Klingmuller, D" uniqKey="Klingmuller D">D Klingmüller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Achermann Jc And Hughes, Ia" uniqKey="Achermann Jc And Hughes I">IA. Achermann JC and Hughes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hook, Eb" uniqKey="Hook E">EB Hook</name></author><author><name sortKey="Warburton, D" uniqKey="Warburton D">D Warburton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bojesan, A" uniqKey="Bojesan A">A Bojesan</name></author><author><name sortKey="Juul, S" uniqKey="Juul S">S Juul</name></author><author><name sortKey="Gravholt, Ch" uniqKey="Gravholt C">CH Gravholt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Parisi, Ma" uniqKey="Parisi M">MA Parisi</name></author><author><name sortKey="Ramsdell, La" uniqKey="Ramsdell L">LA Ramsdell</name></author><author><name sortKey="Burns, Mw" uniqKey="Burns M">MW Burns</name></author><author><name sortKey="Carr, Mc" uniqKey="Carr M">MC Carr</name></author><author><name sortKey="Grady, Re" uniqKey="Grady R">RE Grady</name></author><author><name sortKey="Gunther, Df" uniqKey="Gunther D">DF Gunther</name></author><author><name sortKey="Kletter, Gb" uniqKey="Kletter G">GB Kletter</name></author><author><name sortKey="Mccauley, E" uniqKey="Mccauley E">E McCauley</name></author><author><name sortKey="Mitchell, Me" uniqKey="Mitchell M">ME Mitchell</name></author><author><name sortKey="Opheim, Ke" uniqKey="Opheim K">KE Opheim</name></author><author><name sortKey="Pihoker, C" uniqKey="Pihoker C">C Pihoker</name></author><author><name sortKey="Richards, Ge" uniqKey="Richards G">GE Richards</name></author><author><name sortKey="Soules, Mr" uniqKey="Soules M">MR Soules</name></author><author><name sortKey="Pagon, Ra" uniqKey="Pagon R">RA Pagon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Agha, Ae" uniqKey="Al Agha A">AE Al-Agha</name></author><author><name sortKey="Thomsett, Mj" uniqKey="Thomsett M">MJ Thomsett</name></author><author><name sortKey="Batch, Ja" uniqKey="Batch J">JA Batch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Joshi, Rr" uniqKey="Joshi R">RR Joshi</name></author><author><name sortKey="Rao, S" uniqKey="Rao S">S Rao</name></author><author><name sortKey="Desai, M" uniqKey="Desai M">M Desai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Virtanen, He" uniqKey="Virtanen H">HE Virtanen</name></author><author><name sortKey="Toppari, J" uniqKey="Toppari J">J Toppari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Acerini, Cl" uniqKey="Acerini C">CL Acerini</name></author><author><name sortKey="Miles, Hl" uniqKey="Miles H">HL Miles</name></author><author><name sortKey="Dunger, Db" uniqKey="Dunger D">DB Dunger</name></author><author><name sortKey="Ong, Kk" uniqKey="Ong K">KK Ong</name></author><author><name sortKey="Hughes, Ia" uniqKey="Hughes I">IA Hughes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kumanov, P" uniqKey="Kumanov P">P Kumanov</name></author><author><name sortKey="Tomova, A" uniqKey="Tomova A">A Tomova</name></author><author><name sortKey="Robeva, R" uniqKey="Robeva R">R Robeva</name></author><author><name sortKey="Hubaveshki, S" uniqKey="Hubaveshki S">S Hubaveshki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hassan, Me" uniqKey="Hassan M">ME Hassan</name></author><author><name sortKey="Mustafawi, A" uniqKey="Mustafawi A">A Mustafawi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pang, Sy" uniqKey="Pang S">SY Pang</name></author><author><name sortKey="Wallace, Ma" uniqKey="Wallace M">MA Wallace</name></author><author><name sortKey="Hofman, L" uniqKey="Hofman L">L Hofman</name></author><author><name sortKey="Thuline, Hc" uniqKey="Thuline H">HC Thuline</name></author><author><name sortKey="Dorche, C" uniqKey="Dorche C">C Dorche</name></author><author><name sortKey="Lyon, Ic" uniqKey="Lyon I">IC Lyon</name></author><author><name sortKey="Dobbins, Rh" uniqKey="Dobbins R">RH Dobbins</name></author><author><name sortKey="Kling, S" uniqKey="Kling S">S Kling</name></author><author><name sortKey="Fujieda, K" uniqKey="Fujieda K">K Fujieda</name></author><author><name sortKey="Suwa, S" uniqKey="Suwa S">S Suwa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Clayton, Pe" uniqKey="Clayton P">PE Clayton</name></author><author><name sortKey="Miller, Wl" uniqKey="Miller W">WL Miller</name></author><author><name sortKey="Oberfield, Se" uniqKey="Oberfield S">SE Oberfield</name></author><author><name sortKey="Ritzen, Em" uniqKey="Ritzen E">EM Ritzén</name></author><author><name sortKey="Sippell, Wg" uniqKey="Sippell W">WG Sippell</name></author><author><name sortKey="Speiser Pw Espe Lwpes Cah Working, Group" uniqKey="Speiser Pw Espe Lwpes Cah Working G">Group Speiser PW; ESPE/ LWPES CAH Working</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thyen, U" uniqKey="Thyen U">U Thyen</name></author><author><name sortKey="Lanz, K" uniqKey="Lanz K">K Lanz</name></author><author><name sortKey="Holterhus, Pm" uniqKey="Holterhus P">PM Holterhus</name></author><author><name sortKey="Hiort, O" uniqKey="Hiort O">O Hiort</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Res Pediatr Endocrinol</journal-id><journal-id journal-id-type="publisher-id">JCRPE</journal-id><journal-title-group><journal-title>Journal of Clinical Research in Pediatric Endocrinology</journal-title></journal-title-group><issn pub-type="ppub">1308-5727</issn><issn pub-type="epub">1308-5735</issn><publisher><publisher-name>Galenos Publishing</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21750636</article-id><article-id pub-id-type="pmc">3119445</article-id><article-id pub-id-type="doi">10.4274/jcrpe.v3i2.16</article-id><article-id pub-id-type="pii">96</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Etiological Classification and Clinical Assessment of Children and
Adolescents with Disorders of Sex Development</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Erdoğan</surname><given-names>Sema</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kara</surname><given-names>Cengiz</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Uçaktürk</surname><given-names>Ahmet</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Aydın</surname><given-names>Murat</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label> Department of Pediatric Endocrinology, Ondokuz Mayis University, Samsun, Turkey</aff><pub-date pub-type="ppub"><month>6</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>8</day><month>6</month><year>2011</year></pub-date><volume>3</volume><issue>2</issue><fpage>77</fpage><lpage>83</lpage><history><date date-type="received"><day>22</day><month>12</month><year>2010</year></date><date date-type="accepted"><day>2</day><month>3</month><year>2011</year></date></history><permissions><copyright-statement>© Journal of Clinical Research in Pediatric
Endocrinology, Published by Galenos Publishing.</copyright-statement><copyright-year>2011</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.5/"><license-p>This is an open-access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is
properly cited.</license-p></license></permissions><abstract><p><bold>Objective:</bold> In 2006, the Lawson Wilkins Pediatric Endocrine Society
(LWPES) and the European Society for Paediatric Endocrinology (ESPE) published a
consensus statement on management of intersex disorders. The aim of our study
was to determine the etiological distribution of disorders of sex development
(DSD) according to the new DSD classification system and to evaluate the
clinical features of DSDs in our patient cohort. </p><p><bold>Methods:</bold> We retrospectively reviewed the records of patients
followed up during the past three years. The subjects were divided into three
etiologic groups according to their karyotypes. The definite diagnosesin each
subgroup were established by clinical and laboratory investigations including
abdominopelvic imaging as well as basal and stimulated hormone measurements.
Molecular genetic testing, except for CYP21A2 gene, could not be performed. </p><p><bold>Results:</bold> Out of a total of 95 patients, 26 had sex chromosome DSD,
45 had 46,XY DSD and 24 had 46,XX DSD. The most common causes of DSDs were
Turner’s syndrome (TS), congenital adrenal hyperplasia (CAH) and androgen
insensitivity syndrome (AIS). There was a wide variation in age of presentation
ranging from 1 day to 17.5 years with a mean of 6.5±6.5 years. The most
frequent complaints at presentation were ambiguous genitalia, isolated perineal
hypospadias and short stature. </p><p><bold>Conclusion:</bold> The results of our study demonstrate that the new DSD
classification system leads to a major change in the distribution of etiological
diagnoses of DSDs, which is exemplified by the significant frequencies of TS and
vanishing testes syndrome. This alteration expands the clinical spectrum and
increases the mean age at diagnosis. However, the most common causes of
ambiguous genitalia, such as CAH and AIS, remain unchanged. Further studies
using molecular genetic analyses are needed to give a more precise distribution
of etiologies of DSDs, especially in 46,XY patients.</p><p><bold>Conflict of interest:</bold>None declared.</p></abstract><kwd-group><kwd>Disorders of sex development</kwd><kwd>etiology</kwd><kwd>classification</kwd><kwd>children</kwd><kwd>adolescents</kwd></kwd-group></article-meta></front><body><sec><title>INTRODUCTION</title><p>Disorders of sex development (DSD) are defined as congenital conditions in which
development of chromosomal, gonadal, or anatomical sex is atypical (<xref ref-type="bibr" rid="ref1">1</xref>). In 2006, the Lawson Wilkins Pediatric
Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology
(ESPE) published a consensus statement on management of intersex disorders and
proposed the umbrella term ‘DSD’ instead of terms like
‘intersex’, pseudohermaphroditism (PH)’,
‘hermaphroditism’, ‘sex reversal’, which are often
perceived as pejorative by patients and can be confusing to both health
professionals and parents (<xref ref-type="bibr" rid="ref2">2</xref>,<xref ref-type="bibr" rid="ref3">3</xref>). Besides the new nomenclature, these two
societies proposed a new classification system for causes of DSDs on the basis of
karyotype analysis. The new DSD classification includes three main diagnostic
categories: sex chromosome DSD, 46,XY DSD (formerly male PH) and 46,XX DSD (formerly
female PH). The category of sex chromosome DSD embraces not only ovotesticular DSD
(formerly true hermaphroditism) and 45,X/46,XY mixed gonadal dysgenesis, but also
Turner’s syndrome (TS) and Klinefelter’s syndrome (KS), which are not
included in the previous classifications of intersex disorders (<xref ref-type="bibr" rid="ref4">4</xref>,<xref ref-type="bibr" rid="ref5">5</xref>).
Because the LWPES/ESPE consensus has taken the karyotype as the primary root,
ovotesticular DSD has been classified in three DSD categories - XX, XY and XX/XY.
The new classification also includes disorders such as vanishing testes syndrome and
TS, which are not associated with genital ambiguity at birth. Thus, it would be
expected that the inclusion of such entities into the new classification might lead
to changes in the distribution of etiological diagnoses.</p><p>There are many studies on intersex disorders, whereas, to our knowledge, there are no
data on the frequency of etiological diagnoses based on the new DSD classification
system proposed by the LWPES/ESPE consensus group. Therefore, the aim of our study
was to determine the etiological distribution of DSDs according to the new
classification and to evaluate the clinical features of the most commonly
encountered DSDs in our patient cohort.</p></sec><sec sec-type="materials|methods"><title>MATERIALS AND METHODS</title><p>We retrospectively reviewed the records of patients with DSD followed up during the
past three years at the Department of Pediatric Endocrinology of Ondokuz
Mayıs University. A detailed history including age at presentation, main
complaints, sex of rearing, consanguinity, and family history of similar illness was
taken for each patient. A thorough clinical examination consisting of anthropometry,
assessment of pubertal stage, and presence of hyperpigmentation, hypertension,
associated anomalies or dysmorphic features was made and recorded for each patient.
Prader scoring system and external masculinization score (EMS) were used to
determine the degree of external virilization in 46,XX and 46,XY DSD patients (<xref ref-type="bibr" rid="ref6">6</xref>,<xref ref-type="bibr" rid="ref7">7</xref>).
Criteria suggesting DSD included overt genital ambiguity, apparent female genitalia
with clitoromegaly, posterior labial fusion or inguinal/labial mass, and apparent
male genitalia with non-palpable testes, micropenis, isolated perineal hypospadias
or mild hypospadias with undescended testis (<xref ref-type="bibr" rid="ref2">2</xref>). Also, file records of older children and adolescents who had
incomplete or delayed puberty or primary amenorrhea were retrospectively evaluated
with respect to DSD. Our study also comprised patients with diagnoses such as TS and
KS, which are included in the new DSD classification. Patients with non-congenital
(acquired) problems of late puberty were excluded from this study. </p><p>As a part of routine evaluation of DSD, we performed karyotype analysis,
abdominopelvic ultrasound (if required, magnetic resonance imaging), and hormone
measurements including cortisol, 11-deoxycortisol (11-DOC), 17-hydroxyprogesterone
(17-OHP), dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A), testosterone
(T), dihydrotestosterone (DHT), estradiol (E2) and gonadotropins. When it was
necessary to demonstrate the presence or absence of functioning testicular tissue,
as in the case of patients with suspected ovotesticular DSD and testicular
dysgenesis or anorchia, the levels of anti-Müllerian hormone (AMH) and
inhibin B were measured. We routinely analyze the common mutations in the CYP21A2
gene in congenital adrenal hyperplasia (CAH) patients. However, molecular genetic
testing for mutations in androgen receptor (AR) gene and 5a-reductase gene in
patients with defects in androgen action could not be performed. </p><p>Vanishing testes syndrome was defined as normal virilized external genitalia, no
testosterone response to hCG, and bilateral anorchia detected by imaging studies.
Androgen insensitivity syndrome (AIS) was diagnosed in undervirilized males who had
normal T and DHT response to hCG stimulation and absence of Müllerian
structures. Those with normal female external genitalia were considered as complete
AIS (CAIS) and the rest - as partial AIS (PAIS). Persistent Müllerian duct
syndrome (PMDS) was defined as normal male external genitalia, normal response to
hCG, and presence of Müllerian structures detected by ultrasound. In the
46,XX DSD group, the virilized females were first assessed with respect to basal
(and when indicated, ACTH-stimulated) levels of adrenal steroids and androgens.
Patients with elevated serum levels of 17-OHP and T were diagnosed as CAH. The
diagnosis of CAH due to 21-hydroxylase deficiency was established by a serum 17-OHP
level greater than 100 ng/mL (300 nmol/L) after the first 48 hours and was confirmed
by CYP21A2 gene analysis. Patients with markedly elevated serum levels of 11-DOC and
DHEA-S together with moderately increased serum 17-OHP levels were accepted as
11b-hydroxylase and 3b-hydroxysteroid dehydrogenase deficiencies, respectively.
Virilized females with normal 17-OHP and T levels were categorized as maternal
androgen excess (such as luteoma) or congenital structural abnormality. In these
cases, to exclude ovotesticular DSD, serum levels of AMH and inhibin B were
measured, and imaging of the internal genitalia and gonads was performed. Gonadal
(ovarian) dysgenesis was diagnosed in 46,XX DSD patients who presented with absent
breast development or primary amenorrhea, high gonadotropin levels, and streak
(underdeveloped) gonads detected by imaging studies.</p><p>The data were analyzed using SPSS software (Statistical Package for the Social
Sciences, version 15; SPSS Inc., Chicago, IL, USA). The results are given as
mean±SD or median (range) values, and as percentages, where appropriate.
Comparison between PAIS patients reared as male and those raised as female regarding
EMS was made using the Mann-Whitney U test. A p value of less than 0.05 was
considered statistically significant.</p></sec><sec><title>RESULTS</title><p>A total of 95 patients met the criteria for DSD. There was a wide variation in age at
presentation ranging from 1 day to 17.5 years with a mean age of 6.5±6.5
years. Thirty eight patients presented in infancy, 22 - between 1 and 10 years, and
35 - at ages older than 10 years (<xref ref-type="fig" rid="fg2">Figure 1</xref>). A
history of consanguinity was obtained in 17 cases (18%). The consanguinity
rate in CAH patients (43%) was higher than that in the entire study group. At
the time of presentation, while 37 patients - newborns and young infants - were not
yet assigned a sex of rearing, in the older age groups, 22 patients were raised as
males and 36 as females. A total of 9 patients with a 46,XY karyotype (5 - PAIS, 3
– CAIS, and 1 - 5a-reductase eficiency) had been reared as females, and 2 CAH
patients with 46,XX karyotype as males. All patients in the series were assigned
female or male sex by a gender assessment team composed of pediatric specialists in
endocrinology, surgery, urology and psychiatry as well as medical geneticist. After
gender (re)assignments, the total study group contained 42 males and 53 females. The
main complaints at presentation in DSD patients were ambiguous genitalia
(n=23), short stature (n=19), isolated perineal hypospadias
(n=9), primary amenorrhea (n=8), late or incomplete puberty
(n=8), micropenis (n=6) and clitoromegaly (n=5). Out of a total
of 95 patients, 26 had sex chromosome DSD, 45 had 46,XY DSD and 24 had 46,XX DSD
(<xref ref-type="table" rid="T3">Table 1</xref>). TS (n=21) was the most
common cause (80%) of sex chromosome DSD. There were a few patients with sex
chromosome DSD other than TS, i.e. 45,X/46,XY mixed gonadal dysgenesis (n=3),
45,XX/46,XY ovotesticular DSD (n=1) and 47,XXY, KS (n=1). Patients
with mixed gonadal dysgenesis had overt ambiguous genitalia together with a normal
testis on one side and a streak (dysgenetic) gonad on the contralateral side. These
patients were assigned male sex and their dysgenetic gonads were removed.
Histological examination did not reveal any sign of germ cell malignancies. A
patient presenting with genital ambiguity had Müllerian structures and
bilateral ovotesticular gonads on histological examination. Bilateral gonadectomy
was performed in a 46,XX/46,XY DSD patient who had been reared and assigned as
female. Gonadoblastoma or germinoma were not detected in the removed gonads. The
patient with KS presented with delayed puberty.</p><p>Fifty three percent of patients with TS had 45,X karyotype, and the remaining had
various karyotype abnormalities such as mosaicism (45,X/46,XX;14%),
isochromosome (45,X,i(Xq); 10%) and ring X chromosome (46,X,r(X); 5%).
The mean age at diagnosis for TS patients was 12.1±4.9 years (from
intrauterine period to 17.5 years). Of 21 patients with TS, 16 (76%) had
presented at ages older than 10 years with main complaints of short stature and
primary amenorrhea (<xref ref-type="fig" rid="fg2">Figure 1</xref>). Three patients,
of ages between 1 and 10 years, presented with short stature. One patient was
diagnosed in the newborn period with lymphoedema of the feet, and another one -
incidentally at amniocentesis. The mean height SD score of the TS patients was
-3.82±0.75. Pelvic ultrasound revealed small or no ovarian tissue in all TS
patients. Plasma levels of follicle-stimulating hormone, luteinizing hormone and E2
were 97.3±41.9 (24-170) mIU/mL, 19.7±10.7 (0.15-44) mIU/mL and
11.9±4.4 (5.3-21) pg/mL, respectively. </p><p>Defects in androgen action [AIS (14 partial, 3 complete) and 5a-reductase deficiency
(n=3)] constituted the largest fraction (44%) of the 46,XY DSD group.
Isolated perineal hypospadias (n=9), vanishing testes syndrome (n=6),
micropenis with mild hypospadias or cryptorchidism (n=6) and PMDS
(n=2) were among other diseases in this group (<xref ref-type="table" rid="T3">Table 1</xref>). Two patients’ genital ambiguity was associated
with unidentified syndromes. In our study group, there was no case with 46,XY
gonadal dysgenesis or T biosynthesis defect.</p><p>The mean age at diagnosis for PAIS patients was 5.7±5.9 years (1 day-15.4
years). The ages at presentation were under one year in 6 patients, between 1 and 10
years in 3 patients, and above 10 years in 5 patients (<xref ref-type="fig" rid="fg2">Figure 1</xref>). In both infancy and childhood, the main complaint at
presentation was overt genital ambiguity. However, adolescent patients with PAIS
presented with clitoromegaly, amenorrhea, and incomplete puberty and had already
been reared as females. In addition, three CAIS patients raised as females had
presented with incomplete puberty or primary amenorrhea after 10 years of age. Signs
related to some androgenic effects, such as pubic/axillary hair and phallic
enlargement, differentiated the females with PAIS from those with CAIS. Breast
development and amenorrhea were seen as common clinical features in both patient
groups. Median value of EMSs was 7 (range: 2-10; normal: 0-12) in all PAIS patients.
The median EMS (8.5; range: 4-10) for PAIS patients reared as male was significantly
higher than that (3; range: 2-5) for PAIS patients raised as female
(p<0.001). These scores in patients with CAIS ranged from 1 to 2,
representing the presence of abdominal or inguinal testicles with normal female
external genitalia (<xref ref-type="bibr" rid="ref7">7</xref>). In the entire AIS
group, plasma levels of basal and hCG-stimulated T were 1.17±1.60 (0.08-5.90)
ng/mL and 4.88±2.91 (0.54-12.5) ng/mL, respectively. In all patients with AIS
except two, serum peak T levels were higher than 1 ng/mL. In two patients whose
hCG-stimulated T levels were 0.54 and 0.85 ng/mL, the T/A ratios were 2.6 and 3.2,
respectively. These values were not considered as suggestive of 17b-HSD deficiency.
Also, these patients were not considered as gonadal dysgenesis because of normal
age-matched serum AMH and inhibin B levels and normal-appearing testes by imaging
studies. On the other hand, these two patients were older children who had
undescended testes; thus, incomplete responses to hCG might have been a result of
Leydig cell dysfunction secondary to cryptorchidism. After hCG stimulation, the mean
T/DHT ratio was 10.1±8.2 (2.5-29.1) in the PAIS/CAIS groups. In three
patients accepted as 5a-reductase deficiency, these ratios were 36.3, 54.6 and 66.5.
In addition, serum levels of hCG-stimulated T and T/DHT ratios were normal in the
other 46,XY DSD patients who had isolated perineal hypospadias (n=9) and
micropenis associated with mild glandular hypospadias or cryptorchidism
(n=6). In 46,XY DSD group, there was no patient with congenital
hypogonadotropic hypogonadism.</p><p>The majority of patients with 46,XX DSD had CAH, consisting of 21-hydroxylase
(n=14), 11b-hydroxylase (n=1) and 3b-hydroxysteroid dehydrogenase
(n=1) deficiencies. Four patients presenting with delayed puberty or primary
amenorrhea were diagnosed as 46,XX gonadal dysgenesis. In the other four mildly
virilized newborn females who had isolated clitoromegaly (n=2) or
clitoromegaly with partial labial fusion (n=2), serum hormone measurements
(including 17-OHP, DHEA-S, T, androstenodione, AMH and inhibin B) were in normal
ranges, and abdominopelvic imaging also revealed normal internal genitalia and
gonads. In this group, there was no history of maternal drug intake during
pregnancy; however, one mother had experienced temporary excessive hair growth and
developed acne during the first trimester. The reason of androgenic effect in these
patients could not been completely understood. In a patient whose mother had been
mildly androgenized during pregnancy, the probable cause of virilization was
considered to be a luteoma. The other three patients were categorized as congenital
structural abnormality and were followed up (<xref ref-type="table" rid="T3">Table
1</xref>). </p><p>Out of 14 females with CAH due to 21-hydroxylase deficiency, 9 had salt-wasting type
and 5 had simple virilizing type. The median age at diagnosis for salt wasters was 5
(1-25) days. Patients with simple virilizing CAH presented at median age of 5.3
(1.6-13.1) years with previously unrecognized genital ambiguity and/or virilization.
Two patients from the latter group had been reared as male sex. The oldest one had
heterosexual pseudopuberty and short stature. Hyperpigmentation was detected in six
patients. Median value of Prader scores for patients with 21-hydroxylase deficiency
was 4 (range: 3-5). Plasma levels of 17-OHP and T at diagnosis were 427±332
(227-1200) ng/mL and 6.4±5.9 (0.8-16) ng/mL, respectively. A patient with
11b-OH deficiency had presented at 5.5 years of age with unrecognized genital
ambiguity (Prader 3 virilization), pubic hair and hypertension. Serum levels of
17-OHP, T and 11-DOC were 54 ng/mL, 1.1 ng/mL and >25 ng/mL, respectively. A
female patient presenting with salt wasting and mild clitoromegaly (Prader 2
virilization) at 3 months of age was diagnosed with CAH due to 3b-hydroxysteroid
dehydrogenase deficiency because of increased serum levels of DHEA-S (673
μg/dL), 17-OHP (25 ng/mL) and T (0.87 ng/mL).</p><fig id="fg2" orientation="portrait" position="float"><label>Figure 1</label><caption><title>The age distribution of DSD patients according to their etiologic
diagnoses The most frequent diagnoses of the 95 patients with disorders of
sex development (DSD) were Turner’s syndrome (TS, n=21)
congenital adrenal hyperplasia (CAH, n=16) and partial androgen
insensitivity syndrome (PAIS, n=14). While TS patients were mostly
diagnosed in adolescence, patients with salt-wasting and simple virilizing
CAH were usually seen at infancy and childhood, respectively. PAIS and other
DSD patients were observed in all age groups, with a predominance in infancy
</title></caption><graphic xlink:href="JCRPE-3-77-g1"></graphic></fig><table-wrap id="T3" orientation="portrait" position="float"><label>Table 1</label><caption><title>Etiological classification in 95 patients with DSD</title></caption><graphic xlink:href="JCRPE-3-77-g2"></graphic></table-wrap></sec><sec><title>DISCUSSION</title><p>In 2006, the LWPES and the ESPE published a consensus statement on the management of
‘intersex’ disorders and proposed a new classification for DSD (<xref ref-type="bibr" rid="ref2">2</xref>,<xref ref-type="bibr" rid="ref3">3</xref>).
To our knowledge, to date, there is no study regarding the etiological
classification of DSDs according to the new consensus document. Therefore, this is
the first study evaluating the etiological diagnoses of DSDs according to the new
classification, and we believe it provides some interesting data.</p><p>Firstly, our data demonstrate that the most common causes of DSDs were TS, CAH and
PAIS and, that patients with DSD may present at a wide age range varying from the
first day of life to late adolescence. Our results also indicate that the clinical
manifestations of DSDs are not limited to ambiguous genitalia, but show a broad
spectrum including isolated hypospadias, micropenis, clitoromegaly, incomplete
puberty, amenorrhea and, even, short stature. It is well known that PAIS and CAH are
‘intersex’ disorders associated with genital ambiguity, whereas TS and
46,XX gonadal dysgenesis are not. The results of our study demonstrate that the
inclusion of TS and ovarian dysgenesis into the new etiologic classification of DSD
has been the main factor that expands the clinical spectrum and increases the
average age at diagnosis.The generic term DSD was proposed and defined as congenital
conditions in which development of chromosomal, gonadal or anatomical sex is
atypical (<xref ref-type="bibr" rid="ref1">1</xref>,<xref ref-type="bibr" rid="ref2">2</xref>,<xref ref-type="bibr" rid="ref3">3</xref>). This nomenclature, which
is recommended instead of the word ‘intersex’ referring primarily to
xternal genital ambiguity, may be confusing in the clinical evaluation of patients.
TS, the most frequent diagnosis in our DSD cohort, is a condition in which both
chromosomal and gonadal sex are abnormal despite normal female external genitalia.
Girls with TS are usually diagnosed in late childhood or adolescence when they are
investigated for short stature or delayed puberty. Evaluation of patients with only
ambiguous genitalia for DSD may cause some DSD patients to be overlooked. Therefore,
our study indicates that a number of subjects with short stature and late puberty,
who especially have some dysmorphic features consistent with TS, possibly will be
identified as DSD patients.</p><p>TS is one of the most common sex chromosome abnormalities with an incidence of 1:2000
to 1: 5000 in live-born females (<xref ref-type="bibr" rid="ref10">10</xref>). Thus,
it appears reasonable that in this cohort, TS also constitutes a significant
proportion of DSD cases. In addition, it is noteworthy that we have found only one
patient with KS in our DSD cohort. The number of patients with KS as compared to
those with TS is very low, given its reported incidence ranging between 1:500 and
1:1000 live births (<xref ref-type="bibr" rid="ref11">11</xref>). However, while
girls with TS usually present with short stature in the prepubertal period or with
primary amenorrhea at puberty, the diagnosis of KS is rarely made before puberty
because of paucity or subtleness of clinical manifestations in childhood. It is
likely that a significant proportion of children with mosaic forms of KS or with
milder phenotypes may not have been diagnosed in the age group covered in this
study. </p><p>Approximately fifty percent of the patients in the cohort had 46,XY DSD. This finding
is consistent with other studies (<xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref13">13</xref>,<xref ref-type="bibr" rid="ref14">14</xref>). The most common cause of 46,XY DSD was AIS, either PAIS or CAIS,
representing 44% of 46,XY patients. The percentage of PAIS patients in our
DSD cohort is moderately higher than the results of previous studies (12,13,14),
which can be partly attributed to the fact that we have used a T/DHT ratio as high
as 30 to differentiate 5a-reductase deficiency from AIS. A few patients who had a
value less than 30 might have had 5a-reductase deficiency. In addition, our 46,XY
DSD group included patients with isolated perineal hypospadias and micropenis
without overt genital ambiguity. In these patients, we ruled out a probability of
Leydig cell dysfunction. Such subjects may have been either cases of isolated
anatomical defect of unknown etiology or may represent the milder end of the
spectrum of PAIS (<xref ref-type="bibr" rid="ref9">9</xref>). Therefore, in the
46,XY DSD patients who have normal T production, diagnoses of AIS and 5a-reductase
deficiency need to be confirmed by molecular genetic analyses. </p><p>On the other hand, the identification of a causative AR mutation in PAIS population
is rare (12). In fact, it is possible that patients with CAIS or PAIS in whom no
mutations were found in the AR gene may carry a mutant coactivator protein to
explain the androgen resistance (<xref ref-type="bibr" rid="ref9">9</xref>). Even
though one of the major limitations encountered in our study is the inability to
make definite etiological diagnoses for 46,XY DSD patients, it is true that
undermasculinized patients with normal androgen production (demonstrated by hCG
stimulation) have been exposed to insufficient androgen effects, regardless of the
cause (failure to produce DHT or failure to respond to androgens). Therefore, the
findings of this study suggest that 46,XY DSD mostly results from defects in
androgen action and that androgen biosynthesis defects are rarely seen. However, we
have to emphasize that we have not done genetic analysis in the presumed AIS cases. </p><p>Interestingly, we observed that the frequency of vanishing testes syndrome among
46,XY DSD patients was notably high. These patients presenting with undescended
testes had no genital ambiguity. Because vanishing testes syndrome was not in the
former etiological classifications of intersex disorders (<xref ref-type="bibr" rid="ref4">4</xref>,<xref ref-type="bibr" rid="ref5">5</xref>), its frequency
within DSD is unknown. Cryptorchidism, together with hypospadias, is among the most
common genitourinary anomalies in male children, affecting 1.6% to 9%
live births (<xref ref-type="bibr" rid="ref15">15</xref>). In a recent study, the
prevalence of cryptorchidism at birth was found to be 5.9%, and approximately
one fourth of the patients had non-palpable testes (<xref ref-type="bibr" rid="ref16">16</xref>). Another new population-based study carried out in boys
aged less than one year to 19 years has established that the prevalence of
cryptorchidism was 1.52% (<xref ref-type="bibr" rid="ref17">17</xref>). A
very recent study has shown that about half of the patients with impalpable testes
had vanishing testes syndrome (<xref ref-type="bibr" rid="ref18">18</xref>).
Therefore, we consider that the finding of remarkable frequency of vanishing testes
syndrome in the new DSD classification system is not unexpected. In the 46,XX DSD
group, the most common condition was CAH due to 21-hydroxylase deficiency, a finding
compatible with its worldwide incidence of 1:14 000 live births (<xref ref-type="bibr" rid="ref19">19</xref>). While CAH was identified to occupy
second place in terms of frequency following TS, it was the most common etiology in
patients presenting with genital ambiguity. In fact, CAH is the commonest cause of
ambiguous genitalia of the newborn (<xref ref-type="bibr" rid="ref20">20</xref>). In
an epidemiological study, the incidence of ambiguous genitalia in neonates was
identified as 1:5 000 births, and the most common diagnosis was CAH, followed by AIS
and mixed gonadal dysgenesis (<xref ref-type="bibr" rid="ref21">21</xref>). Our
results are in agreement with this study and suggest that CAH remains the most
common cause of ambiguous genitalia, regardless of the classification system used in
DSD.In conclusion, this study reveals that the new DSD classification system leads
to a major change in the distribution of etiological diagnoses of DSDs, which is
exemplified by the significant frequencies of TS and vanishing testes syndrome.
However, the most common causes of ambiguous genitalia such as CAH and AIS remain
unchanged. Further studies using molecular genetic analyses are needed to give a
more precise distribution of etiologies of DSDs, especially in 46,XY patients.</p></sec></body><back><ref-list><title>References</title><ref id="ref1"><label>1</label><element-citation publication-type="journal" publication-format="online"><person-group person-group-type="author"><name><surname>Hughes</surname><given-names>IA</given-names></name></person-group><article-title>Disorders of sex development: a new definition and
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