Disorders of Sex Development: Timing of Diagnosis and Management in A Single Large Tertiary Center
Disorders of Sex Development: Timing of Diagnosis and Management in A Single Large Tertiary Center
Disorders of Sex Development: Timing of Diagnosis and Management in A Single Large Tertiary Center
RESEARCH
Abstract
Background: We describe the phenotypic spectrum and timing of diagnosis and Key Words
management in a large series of patients with disorders of sexual development (DSD) ff disorders of sex
treated in a single pediatric tertiary center. development
Methods: DSD patients who had visited our tertiary center during the survey period ff Turner syndrome
(between 2004 and 2014) were identified based on an ICD-10 inquiry, and their ff Klinefelter syndrome
phenotypic and molecular genetic findings were recorded from patient charts. ff cryptorchidism
Results: Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex ff children
chromosome DSD and 9.6% had 46,XX DSD. The most common diagnoses were Turner
syndrome (19.8%, diagnosed at the mean age of 4.7 ± 5.5 years), Klinefelter syndrome
(14.5%, 6.8 ± 6.2 years) and bilateral cryptorchidism (23.1%). Very few patients with
46,XY DSD (7%) or 46,XX DSD (21%) had molecular genetic diagnosis. The yearly rate of
DSD diagnoses remained stable over the survey period. After the release of the Nordic
consensus on the management of undescended testes, the age at surgery for bilateral
cryptorchidism declined significantly (P < 0.001).
Conclusions: Our results show that (i) Turner syndrome and Klinefelter syndrome, the
most frequent single DSD diagnoses, are still diagnosed relatively late; (ii) a temporal
shift was observed in the management of bilateral cryptorchidism, which may favorably
influence patients’ adulthood semen quality and (iii) next-generation sequencing
Endocrine Connections
methods are not fully employed in the diagnostics of DSD patients. (2018) 7, 595–603
Background
Disorders of sexual development (DSD) are congenital especially, hypospadias and undescended testes have
conditions in which the chromosomal, anatomic or been linked to the actions of environmental agents (3).
gonadal sex development is atypical (1). Today, DSD A family history with genital abnormalities, delayed
is classified into three major categories by the patient’s puberty, infertility, stillbirths or multiple miscarriages
karyotype: sex chromosome DSD, 46,XY DSD and 46,XX should lower the threshold for molecular genetic
DSD (1). The phenotypic spectrum of DSD is wide, and it investigations (4). A newborn with ambiguous genitalia
can manifest as a complete sex reversal, a solitary genital requires evaluation by a multidisciplinary team that aims
abnormality or it can be a part of a syndrome affecting to determine the sex of rearing, and eventually designs a
other organ systems (2). The etiology of DSD is multifaceted long-term management plan in close co-operation with
and can be caused by genetic and environmental factors; the patient and the family (1). It is generally agreed that
http://www.endocrineconnections.org ©2018 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0070 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International
License.
E Kohva et al. DSDs: timing of diagnosis and 7:4 596
management
timely diagnosis and management are important as they or a pediatric surgeon in the patient data system on either
potentially prevent adverse health outcomes and improve clinical or molecular genetic DSD diagnosis. Patients over
long-term, health-related quality of life (5, 6, 7, 8, 9, 10). 20 years old and patients with unilateral cryptorchidism,
There are currently only a handful of systematic and distal hypospadias, epispadias, chordee, cloaca, congenital
comprehensive reports on the etiology and management of rectovaginal fistula, imperforate hymen, bifid clitoris or
DSD patients (11, 12, 13, 14, 15, 16, 17). At the same time, fusion of labia were excluded from the analyses. Boys with
there is a vivid ongoing global debate on the treatment congenital adrenal hyperplasia (CAH) were not considered
policies of these patients (4, 14, 18, 19, 20). The first step DSD patients since no DSD phenotype was present.
toward evidence-based, optimal care of this patient group We paid special attention to patients who had either
would be to describe the current status of diagnostics and Turner syndrome (TS) or Klinefelter syndrome (KS). The
management in pediatric tertiary centers. In this study, we ICD-10 inquiry returned originally 134 patients with
describe the phenotypic spectrum and molecular genetic TS diagnosis. Manual verification of the patient records
findings of DSD patients treated at the Helsinki University revealed, however, that 25 of them did not meet the
Hospital between 2004 and 2014, with special attention definition for TS (9) and therefore 109 TS patients were
on the timing of diagnosis and management of the most included in the analyses. Similarly, we excluded 5 of the
prevalent DSDs. 85 KS patients identified by the original ICD-10 inquiry,
as they were found not to meet the criteria for KS (22).
The age at diagnosis was available for 90% (n = 98) of TS
Patients and methods patients and 85% (n = 68) KS patients. Approximately half
of TS (51%) and KS (55%) patients were diagnosed during
We performed an ICD-10 code-based inquiry covering the study period.
the years from 2004 to 2014 to the electronic patient To study the management of bilateral cryptorchidism,
information system of the Helsinki University Hospital, we evaluated all 46,XY DSD patients retrieved by the
the tertiary center of the Helsinki metropolitan area ICD-10 search (Table 1). The patient records of boys referred
(catchment area 1.2 million people in 2014, 0.3 million of for isolated bilateral cryptorchidism or a more complex
which were children and adolescents 0–20 years old (21)) phenotype accompanied by bilaterally undescended testes
also nationally responsible for treating severe and rare were reviewed. The age at bilateral orchiopexy or the first
illnesses. We included diagnoses describing phenotypes of the two unilateral orchiopexies was recorded for each
with deviations in chromosomal, gonadal or phenotypic boy and used in subsequent analyses.
sexual development. To examine the relation of minor
anatomic deviations to actual DSDs, we accepted a
wide range of diagnoses (i.e. distal hypospadias and/or Statistical analyses
unilateral cryptorchidism) in the search (Table 1). We
Correlations between variables were assessed with
identified altogether 3206 patients who had visited the
Spearman rank correlation analysis. Mann–Whitney
Pediatric, Pediatric Endocrine and/or Pediatric Surgical
U test and chi-square test were used to compare the ages
Clinics for the evaluation of treatment of DSD or a minor
of boys with bilateral cryptorchidism operated between
anatomic deviation. The selection of these outpatient
2004 and 2007 or 2008 and 2014. The data in the text
clinics was based on their clinical practice: every DSD
are presented with a mean ± s.d. and the data in the tables
patient visits either pediatrician, pediatric endocrinologist
as median (range) unless otherwise stated. P < 0.05 was
or pediatric surgeon. Data from other departments (i.e.
accepted to indicate statistical significance.
genetics) were utilized, if available. In the more thorough
examination, we included patients with ICD-10 diagnoses
describing DSD phenotypes as defined by the LWPES/ESPE
consensus group in 2006 (1), and hence, also accepted Results
bilateral cryptorchidism and penoscrotal or perineal
Phenotypic spectrum of DSD patients and timing
hypospadias. We reviewed the electronic patient records
of diagnosis
of these patients (n = 885) for clinical features, karyotype
and molecular genetics to verify their diagnoses and record We identified 3206 patients who were evaluated for one or
their family anamnesis (Fig. 1). The date of diagnosis was multiple ICD-10 diagnosis of interest in either Pediatric,
defined as the first remark by a pediatric endocrinologist Pediatric Endocrine and/or Pediatric Surgery Outpatient
http://www.endocrineconnections.org ©2018 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0070 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International
License.
E Kohva et al. DSDs: timing of diagnosis and 7:4 597
management
46,XY DSD
E34.5 Androgen insensitivity syndrome
Q53.2 Undescended testicle, bilateral
Q54.2 Hypospadias, penoscrotal
Q54.3 Hypospadias, perineal
Q55.00 Absence and aplasia of testis
Q55.01 Anorchia
Q56.1 Male pseudohermaphroditism, not elsewhere classified
Q97.3 Female with 46,XY karyotype
46,XX DSD
Q52.0 Congenital absence of vagina
Q52.1 Doubling of vagina
Q56.2 Female pseudohermaphroditism, not elsewhere classified
Q98.3 Other male with 46,XX karyotype
E25.00 Salt-losing congenital adrenal hyperplasia
E25.01 Congenital adrenal hyperplasia
Sex chromosome DSD
Q96.0-Q96.9 Turner syndrome and variants
Q97.0-Q97.9 Other sex chromosome abnormalities, female phenotype, not elsewhere classified
Q98.0,Q98.1
Q98.2,Q98.4 Klinefelter syndrome and variants
Q98.5-Q98.9 Other sex chromosome abnormalities, male phenotype, not elsewhere classified
Unspecified DSD
E25.9 Adrenogenital disorder, unspecified
Q56.0 Hermaphroditism, not elsewhere classified
Q56.3 Pseudohermaphroditism, unspecified
Q56.4 Indeterminate sex, unspecified
Other diagnoses
Q53.0 Ectopic testis
Q53.1 Undescended testicle, unilateral
Q53.9 Undescended testicle, unspecified
Q54.0 Hypospadias, balanic
Q54.1 Hypospadias, penile
Q54.4 Congenital chordee
Q54.8 Other hypospadias
Q54.9 Hypospadias, unspecified
Q55.1 Hypoplasia of testis and scrotum
Q55.20 Retractile testis
Q55.28 Unspecified congenital malformations of testis and scrotum
Q55.6 Other congenital malformations of penis
Q55.8 Other specified congenital malformations of male genital organs
Q55.9 Congenital malformation of male genital organ, unspecified
Q52.2 Congenital rectovaginal fistula
Q52.3 Imperforate hymen
Q52.4 Other congenital malformations of vagina
Q52.5 Fusion of labia
Q52.8 Other specified congenital malformations of female genitalia
Q52.9 Congenital malformation of female genitalia, unspecified
Q64.1 Exstrophy of urinary bladder
Q43.7 Persistent cloaca
Clinics at the Helsinki University Hospital between 2004 Only 21% of 46,XX DSD patients and 7% of 46,XY DSD
and 2014. Over two-thirds of these patients (72%) had patients had a molecular genetic diagnosis, and none
minor deviations of the genitourinary tract that are not of those were made with next-generation sequencing
classified as DSDs (Fig. 1 and Table 1). Patients with a DSD methods. Even in patients with a distinct phenotype,
diagnosis (n = 550) were divided into three karyotype- such as persistent Müllerian duct syndrome, the diagnosis
based subgroups as suggested in the Chicago consensus was seldom confirmed genetically. Age at diagnosis
statement (1); 53.3% had 46,XY DSD; 37.1% had sex was available for 75% of 46,XY DSD patients, 86% of
chromosome DSD and 9.6% had 46,XX DSD (Fig. 1). 46,XX DSD patients and 87% of sex chromosome DSD
http://www.endocrineconnections.org ©2018 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0070 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International
License.
E Kohva et al. DSDs: timing of diagnosis and 7:4 598
management
Figure 1
Inclusion criteria and outcomes. Patients retrieved
from the ICD-10 inquiry (n = 3206) and DSD
patients (n = 550) included in the analyses, divided
into three subgroups based on ‘Consensus
statement on management of intersex
disorders’ (1).
patients. Table 2 shows detailed distribution and timing patients who had been diagnosed before 2004 and
of diagnoses among these DSD patients; most common had follow-up visits during the survey period. The
diagnoses were bilateral cryptorchidism (23.1%), TS annual number of new DSD patients remained stable
(19.8%) and KS (14.5%). The mean age at diagnosis was (26 ± 7 patients per year; mean ± s.d., range 10–40) and
2.2 ± 3.8 years for 46,XY DSD, 2.4 ± 4.6 years for 46,XX did not correlate with time (r = 0.18, P = 0.6, n = 11). No
DSD and 5.3 ± 5.8 years for sex chromosome DSD. In significant trends in the annual number of patients were
the majority of patients with 46,XY DSD or 46,XX DSD observed either when estimated separately in subgroups
the diagnosis, based on phenotype or molecular genetic of 46,XY DSD (range 5–24, r = 0.31, P = 0.4, n = 11), sex
finding, was made immediately after birth, apart from chromosome DSD (range 5–15, r = −0.43, P = 0.18, n = 11)
46,XX DSD patients expressing SRY and those presenting and 46,XX DSD (range 0–6, r = −0.50, P = 0.12, n = 11).
DSD as part of a syndrome.
Consanguinity was seldom reported in our data:
Timing of diagnosis in sex chromosome DSDs:
only in two families, the parents were either first or
Turner syndrome and Klinefelter syndrome
second cousins. Two families with multiple DSD cases
were identified. One family presented with several cases Our data allowed us to estimate the age at diagnosis of (TS)
of persistent Müllerian duct syndrome. In the other and (KS) (Fig. 2). For the 80 boys with KS, the diagnosis
family, there were two brothers with a DSD phenotype was set at the mean age of 6.8 ± 6.2 years mostly due to
of unknown etiology (one brother had a micropenis with specific language impairment and/or learning difficulties
proximal hypospadias and a vaginal remnant and the (40%), delayed motor development (13%) or small testicles
other proximal hypospadias). In addition, three families (11%). Twelve boys were diagnosed already before birth
where the DSD patient’s sibling had a minor anatomic (Fig. 2). Boys referred for evaluation due to developmental
deviation were identified. issues were aged 8.0 ± 3.5 years, and boys detected due
We next investigated the annual number of new to small testicular size 15.8 ± 1.3 years. Klinefelter boys
DSD patients between 2004 and 2014 (n = 290), excluding diagnosed after birth were most frequently referred from
http://www.endocrineconnections.org ©2018 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0070 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International
License.
E Kohva et al. DSDs: timing of diagnosis and 7:4 599
management
Table 2 Classification of DSD patients (n = 550) by molecular diagnosis or phenotype, age at diagnosis and rate of molecular
genetic diagnoses.
46,XY DSD
(A) Disorders of gonadal development
1. Gonadal regression 27 (4.9) 0.84 (0.01–14.9) 0
2. Ovotesticular DSD 2 (0.4) 7.9 (0.04–15.7) 0
(B) Disorders in androgen synthesis or action
1. Androgen biosynthesis defect (3BHSD) 1 (0.2) NA 0
2. Defect in androgen action (AIS) 5 (0.9) 7.7 (0–15.3) 20
3. Disorders of AMH of AMH-receptor (persistent Müllerian 7 (1.3) 0.7 (0–2.4) 29
duct syndrome)
(C) Other
1. Unknown male undermasculinization
Bilateral cryptorchidism 125 (22.7) 0.9 (0–16.1) 9
Severe hypospadias 55 (10.0) 0.01 (0–1.7) 0
Severe hypospadias and bilateral cryptorchidism 16 (2.9) 0.02 (0–0.04) 0
Micropenis 5 (0.9) 0.01 (0–10.6) 0
Micropenis and bilateral cryptorchidism 6 (1.1) 0.1 (0–10.5) 20
Micropenis and severe hypospadias 8 (1.5) 0.01 (0–0.4) 0
Micropenis, bilateral cryptorchidism and severe hypospadias 4 (0.7) 0 (0–0.1) 0
2. Part of a syndrome (e.g. Prune Belly, Prader–Willi, Noonan) 19 (3.5) 0.02 (0–11.5) 42
3. Cloacal extrophy 13 (2.4) 0.0 0
46,XX DSD
(A) Disorders of gonadal development
1. Ovotesticular DSD 1 (0.2) 0.0 0
2. SRY + 4 (0.7) 6.3 (0.3–18.1) 100
(B) Androgen excess
1. CAH 31 (5.6) 0.0 (0–8.8) 23
(C) Other
1. Congenital structural abnormalities (e.g. vagina duplex, 5 (0.9) 0.05 (0–10.6) 0
vaginal atresia, clitoris hyperplasia)
2. Part of a syndrome (e.g. MRKH, HFGS) 6 (1.1) 6.4 (0–15.4) 0
3. Cloacal extrophy 6 (1.1) 0.0 0
Sex chromosome DSD
(A) Turner syndrome and variants 109 (19.8) 2.1 (0–17.0)
(B) Klinefelter syndrome and variants 80 (14.5) 6.7 (0–17.4)
(C) 45,X/ 46,XY mixed gonadal dysgenesis, ovotesticular DSD 14 (2.5) 0.0 (0–10.1)
(D) Other
Structural anomaly of Y chromosome and testis retention 1 (0.2) 0.07
the local healthcare center (24%), maternity hospital (9%) Timing of management in bilateral cryptorchidism
or department of pediatric neurology (9%).
The girls with TS (n = 109) were diagnosed at the Finally, we reviewed the changes in the management of
mean age of 4.7 ± 5.5 years. The age distribution was cryptorchidism by estimating the age at operation for
skewed as twenty-five girls were diagnosed prenatally, bilateral cryptorchidism before (years 2004–2007) and
and, in 47% of the cases, diagnosis was reached by the following the release of the Nordic consensus (years
age of one year (Fig. 2). Turner girls diagnosed after 2008–2014) on treatment of undescended testes (8).
birth were most frequently referred by child health Altogether, during the whole study period (2004–2014),
care clinic (19%), maternity hospital (16%) or another 142 patients were operated and the average age of
hospital district (6%). The main complaint (41% of all operation for bilateral cryptorchidism was 45.1 ± 44.8
cases) was delayed growth. There were no significant months. The annual number of operated patients (range
trends in the age at diagnosis in either KS or TS patient 8–17) did not increase significantly during the survey
groups between 2004 and 2014 (KS range 0–17 year, period (R = 0.41, P = 0.21, n = 11). However, the age at
r = 0.05, P = 0.75, n = 44; TS range 0–17 year, r = 0.003, operation declined after the release of the consensus from
P = 0.98, n = 56). 54.5 ± 43.0 months to 41.1 ± 45.3 months (P = 0.0001).
http://www.endocrineconnections.org ©2018 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0070 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International
License.
E Kohva et al. DSDs: timing of diagnosis and 7:4 600
management
Figure 2
Percentage of TS (n = 98) and KS (n = 68) patients
diagnosed per age group. Data obtained from
patients visiting the outpatient clinics of a single
tertiary center between 2004 and 2014 whose
age at diagnosis was available.
Indeed, before the Nordic consensus statement, are few. In our series, approximately half of the patients
all bilateral cases (n = 42) were operated after the age of had 46,XY DSD, whereas only one-tenth (9.6%) had 46,XX
1 year but after 2007, almost one-third (28 of 100 boys) DSD. The proportion of 46,XY DSD patients is similar to
was operated before the age of 1 year (P = 0.0001, Fig. 3). the results reported from Turkey (47%) (12), South Africa
To exclude boys with acquired cryptorchidism and cases (57%) (13) and North India (52.5%) (17), and somewhat
of congenital cryptorchidism missed in early childhood, lower than has been reported from Indonesia (68%) (16).
we limited the analysis to those boys operated before the On the other hand, our series contained more cases with
age of three (23). In this subanalysis, the age at operation sex chromosome DSDs than the previously mentioned
had declined from 24.5 ± 5.4 months in boys operated reports, which may reflect differences in prenatal
between 2004 and 2007 to 13.7 ± 5.3 months in those screening policies. Of note, in a recent Danish nationwide
operated after 2007 (P < 0.0001). study, the estimated prevalence of androgen insensitivity
syndrome was 2.3 per 100,000 live born females (24),
which appears close to our frequency estimate based
on the current catchment area of our tertiary center. In
Discussion
our study, congenital adrenal hyperplasia (CAH) was
Attempts to estimate the etiological distribution of DSDs expectedly the most common cause of 46,XX DSD. After
according to the 2006-launched DSD classification system the implementation of the newborn screening in Finland
Figure 3
Age at orchiopexy. Age at bilateral orchiopexy or
first of the two unilateral orchiopexies in a single
tertiary center in 142 boys operated between
2004 and 2014. 42 boys were operated between
2004 and 2007 before the release of the Nordic
consensus on treatment of undescended testes (8)
and 100 boys thereafter.
http://www.endocrineconnections.org ©2018 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0070 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International
License.
E Kohva et al. DSDs: timing of diagnosis and 7:4 601
management
in 2015, six new CAH patients have been diagnosed by boy with bilateral cryptorchidism was operated before the
it. We anticipate that screening leads to better diagnostic age of one year in our hospital, whereas thereafter, the age
yield and conceivably better care for this patient group in at orchiopexy has decreased at least by 10 months. Our
the future. finding is in line with the results published from Sweden
Since early diagnosis of DSD is considered important and Norway (34, 35).
(7, 25, 26), the efficacy of the diagnostic procedures of In this cohort, 21% of patients with 46,XX DSD and
most frequent patient groups merits evaluation. The mean only 7% of 46,XY DSD were diagnosed genetically. In the
age at diagnosis of TS patients in our series was 4.7 years, largest patient group of 46,XX DSD, CAH, the current
a result similar to the findings reported from the United standard of diagnostics is still based on steroid hormone
States and Spain (26, 27). A quarter of our TS patients was and other biochemical analyses instead of molecular
diagnosed prenatally, based on the voluntary, combined genetics (36). For 46,XY DSD boys, it seems that the
first trimester screening (a nuchal translucency scan etiology remains largely unknown in the clinical setting.
and maternal serum screening followed by a prenatal In the research setting, however, the overall genetic
chromosome test, if necessary). After birth, the most diagnostic rate achieved with a targeted DSD gene panel,
frequent symptom guiding to diagnosis was short stature can increase up to 43% (37). An accurate molecular genetic
(41%), the leading clinical cue also in other studies (26, diagnosis is probably valuable in planning the long-term
27). The diagnosis of KS patients in our series was even treatment of the patient, although more research is needed
further delayed, and the diagnosis was typically suspected to show if the ever more precise diagnostics is associated
during childhood due to developmental problems, and with beneficial changes in clinical practice from the
during adolescence due to small testicular size. If the patient’s perspective (38). While awaiting such evidence,
frequency of KS was 1/667 male births in our area (28), it is still reasonable to conclude that the molecular genetic
we could roughly estimate that, between 2004 and 2006, diagnostic rate should be improved by applying NGS
~20–30% of the boys with KS were diagnosed before the methodology.
age of 8 years. This low diagnostic yield is in agreement Our retrospective study has certain limitations. The
with the Danish data suggesting that only 10% of Danish ICD-10 classification has multiple different diagnosis
KS patients are diagnosed before the age of 14 years codes describing the same phenomenon. To overcome
(29). One possibility to expedite diagnostics would be to this, we evaluated the patient records and chose the
include sex chromosome abnormalities in the national diagnostic code, which best described the patient’s
newborn screening programs, an idea that has been well- phenotype. Moreover, often there are no specific ICD-10
taken by parents of KS patients and pediatricians (10, 30). codes reserved for rare genetic diseases.
Also peer groups of TS (e.g. Turner Syndrome Society of
the United States) are in favor of diagnosing TS as early
as possible in order to anticipate the possible need of
Conclusions
services required for variable defects in childhood (31).
On the other hand, many pregnancies, in which TS is We present data from one of the largest series of DSD
prenatally diagnosed, are currently terminated, although patients to date. Analysis of patients with chromosomal
the severity of the TS phenotype is hard to predict and a DSD shows that patients with TS or KS are diagnosed
postnatal re-evaluation of chromosomes is needed for an relatively late and often the initiative for the diagnostic
accurate diagnosis (9, 31). workup is related to special needs of the patients (KS)
The timing of orchiopexy is highly variable, and for or deceleration of growth (TS). It is feasible that age at
example, 95% of surgeries were performed after the first diagnosis in patients with TS or KS and the age at operation
year of life in German hospitals (32), and in Singapore, the of bilateral cryptorchidism could serve as indices for
corresponding number was 70% (33). Nordic guidelines monitoring the diagnostic efficiency and management
for the treatment of cryptorchidism were renewed at 2007 of DSD patients within and between different tertiary
and accordingly the age for orchiopexy was advanced to centers providing care for this vulnerable patient group.
6–12 months (8). We tested whether implementation of the
guideline in our tertiary center functions as an indicator
Declaration of interest
for standard of care. Between 2004 and 2007, before the The authors declare that there is no conflict of interest that could be
release of the Nordic consensus statement (8), not a single perceived as prejudicing the impartiality of the research reported.
http://www.endocrineconnections.org ©2018 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0070 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International
License.
E Kohva et al. DSDs: timing of diagnosis and 7:4 602
management
http://www.endocrineconnections.org ©2018 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0070 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International
License.
E Kohva et al. DSDs: timing of diagnosis and 7:4 603
management
25 Hersmus R, Stoop H, White SJ, Drop SLS, Oosterhuis JW, Incrocci L, observational analysis of 3587 cases. BMC Pediatrics 2015 15 116.
Wolffenbuttel KP & Looijenga LHJ. Delayed recognition of disorders (https://doi.org/10.1186/s12887-015-0429-1)
of sex development (DSD): a missed opportunity for early diagnosis 33 Nah SA, Yeo CSW, How GY, Allen JC, Lakshmi NK, Yap T-L,
of malignant germ cell tumors. International Journal of Endocrinology Jacobsen AS, Low Y & Ong CC. Undescended testis: 513 patients’
2012 2012 671209. characteristics, age at orchidopexy and patterns of referral. Archives
26 Sävendahl L & Davenport ML. Delayed diagnoses of Turner’s of Disease in Childhood 2014 99 401–406. (https://doi.org/10.1136/
syndrome: proposed guidelines for change. Journal of Pediatrics 2000 archdischild-2013-305225)
137 455–459. (https://doi.org/10.1067/mpd.2000.107390) 34 Bergbrant S, Omling E, Björk J & Hagander L. Cryptorchidism in
27 Ríos Orbañanos I, Vela Desojo A, Martinez-Indart L, Grau Bolado G, Sweden: a nationwide study of prevalence, operative management,
Rodriguez Estevez A & Rica Echevarria I. Turner syndrome: from and complications. Journal of Pediatrics 2018 194 197–203.e6.
birth to adulthood. Endocrinología y Nutrición 2015 62 499–506. (https://doi.org/10.1016/j.jpeds.2017.09.062)
(https://doi.org/10.1016/j.endonu.2015.06.010) 35 Nilsson R, Omland H, Dahl AA & Johansen TEB. Early outcome of
28 Bojesen A, Juul S & Gravholt CH. Prenatal and postnatal prevalence orchiopexy and analysis of predictive factors: a retrospective study
of Klinefelter syndrome: a national registry study. Journal of Clinical from 2001 to 2010 in a Norwegian regional hospital. Scandinavian
Endocrinology and Metabolism 2003 88 622–626. (https://doi. Journal of Urology 2014 48 474–481. (https://doi.org/10.3109/216818
org/10.1210/jc.2002-021491) 05.2014.905631)
29 Groth KA, Skakkebæk A, Høst C, Gravholt CH & Bojesen A. 36 Kulle A, Krone N, Holterhus PM, Schuler G, Greaves RF, Juul A, de
Clinical review: Klinefelter syndrome – a clinical update. Journal of Rijke YB, Hartmann MF, Saba A, Hiort O, et al. Steroid hormone
Clinical Endocrinology and Metabolism 2013 98 20–30. (https://doi. analysis in diagnosis and treatment of DSD: position paper of EU
org/10.1210/jc.2012-2382) COST Action BM 1303 'DSDnet'. European Journal of Endocrinology
30 Herlihy AS & McLachlan RI. Screening for Klinefelter syndrome. 2017 176 P1–P9. (https://doi.org/10.1530/EJE-16-0953)
Current Opinion in Endocrinology, Diabetes and Obesity 2015 22 37 Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T,
224–229. (https://doi.org/10.1097/MED.0000000000000154) Hewitt J, Lambeth L, Bouty A, Knarston IM, Tan TY, et al. Disorders
31 Baena N, De Vigan C, Cariati E, Clementi M, Stoll C, Caballín MR & of sex development: insights from targeted gene sequencing of a
Guitart M. Turner syndrome: evaluation of prenatal diagnosis in 19 large international patient cohort. Genome Biology 2016 17 243.
European registries. American Journal of Medical Genetics Part A 2004 (https://doi.org/10.1186/s13059-016-1105-y)
129A 16–20. (https://doi.org/10.1002/ajmg.a.30092) 38 Alhomaidah D, McGowan R & Ahmed SF. The current state of
32 Hensel KO, Caspers T, Jenke AC, Schuler E & Wirth S. Operative diagnostic genetics for conditions affecting sex development. Clinical
management of cryptorchidism: guidelines and reality – a 10-year Genetics 2017 91 157–162. (https://doi.org/10.1111/cge.12912)
http://www.endocrineconnections.org ©2018 The authors This work is licensed under a Creative Commons
https://doi.org/10.1530/EC-18-0070 Published by Bioscientifica Ltd Attribution-NonCommercial 4.0 International
License.