Disorders of sex development: timing of diagnosis and management in a single large tertiary center

in Endocrine Connections
Authors:
E Kohva Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Faculty of Medicine, Department of Physiology, University of Helsinki, Helsinki, Finland

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P J Miettinen Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

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S Taskinen Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Department of Pediatric Surgery, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

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M Hero Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

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A Tarkkanen Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Faculty of Medicine, Department of Physiology, University of Helsinki, Helsinki, Finland

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T Raivio Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Faculty of Medicine, Department of Physiology, University of Helsinki, Helsinki, Finland

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Background

We describe the phenotypic spectrum and timing of diagnosis and management in a large series of patients with disorders of sexual development (DSD) treated in a single pediatric tertiary center.

Methods

DSD patients who had visited our tertiary center during the survey period (between 2004 and 2014) were identified based on an ICD-10 inquiry, and their phenotypic and molecular genetic findings were recorded from patient charts.

Results

Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex 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 methods are not fully employed in the diagnostics of DSD patients.

Abstract

Background

We describe the phenotypic spectrum and timing of diagnosis and management in a large series of patients with disorders of sexual development (DSD) treated in a single pediatric tertiary center.

Methods

DSD patients who had visited our tertiary center during the survey period (between 2004 and 2014) were identified based on an ICD-10 inquiry, and their phenotypic and molecular genetic findings were recorded from patient charts.

Results

Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex 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 methods are not fully employed in the diagnostics of DSD patients.

Background

Disorders of sexual development (DSD) are congenital conditions in which the chromosomal, anatomic or gonadal sex development is atypical (1). Today, DSD is classified into three major categories by the patient’s karyotype: sex chromosome DSD, 46,XY DSD and 46,XX DSD (1). The phenotypic spectrum of DSD is wide, and it can manifest as a complete sex reversal, a solitary genital abnormality or it can be a part of a syndrome affecting other organ systems (2). The etiology of DSD is multifaceted and can be caused by genetic and environmental factors; especially, hypospadias and undescended testes have been linked to the actions of environmental agents (3). A family history with genital abnormalities, delayed puberty, infertility, stillbirths or multiple miscarriages should lower the threshold for molecular genetic investigations (4). A newborn with ambiguous genitalia requires evaluation by a multidisciplinary team that aims to determine the sex of rearing, and eventually designs a long-term management plan in close co-operation with the patient and the family (1). It is generally agreed that timely diagnosis and management are important as they potentially prevent adverse health outcomes and improve long-term, health-related quality of life (5, 6, 7, 8, 9, 10).

There are currently only a handful of systematic and comprehensive reports on the etiology and management of DSD patients (11, 12, 13, 14, 15, 16, 17). At the same time, there is a vivid ongoing global debate on the treatment policies of these patients (4, 14, 18, 19, 20). The first step toward evidence-based, optimal care of this patient group would be to describe the current status of diagnostics and management in pediatric tertiary centers. In this study, we describe the phenotypic spectrum and molecular genetic findings of DSD patients treated at the Helsinki University Hospital between 2004 and 2014, with special attention on the timing of diagnosis and management of the most prevalent DSDs.

Patients and methods

We performed an ICD-10 code-based inquiry covering the years from 2004 to 2014 to the electronic patient information system of the Helsinki University Hospital, the tertiary center of the Helsinki metropolitan area (catchment area 1.2 million people in 2014, 0.3 million of which were children and adolescents 0–20 years old (21)) also nationally responsible for treating severe and rare illnesses. We included diagnoses describing phenotypes with deviations in chromosomal, gonadal or phenotypic 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 unilateral cryptorchidism) in the search (Table 1). We identified altogether 3206 patients who had visited the Pediatric, Pediatric Endocrine and/or Pediatric Surgical Clinics for the evaluation of treatment of DSD or a minor anatomic deviation. The selection of these outpatient clinics was based on their clinical practice: every DSD patient visits either pediatrician, pediatric endocrinologist or pediatric surgeon. Data from other departments (i.e. 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 bilateral cryptorchidism and penoscrotal or perineal hypospadias. We reviewed the electronic patient records of these patients (n = 885) for clinical features, karyotype and molecular genetics to verify their diagnoses and record their family anamnesis (Fig. 1). The date of diagnosis was defined as the first remark by a pediatric endocrinologist or a pediatric surgeon in the patient data system on either clinical or molecular genetic DSD diagnosis. Patients over 20 years old and patients with unilateral cryptorchidism, distal hypospadias, epispadias, chordee, cloaca, congenital rectovaginal fistula, imperforate hymen, bifid clitoris or fusion of labia were excluded from the analyses. Boys with congenital adrenal hyperplasia (CAH) were not considered DSD patients since no DSD phenotype was present.

Figure 1
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).

Citation: Endocrine Connections 7, 4; 10.1530/EC-18-0070

Table 1

ICD-10 diagnoses included in the inquiry.

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

We paid special attention to patients who had either Turner syndrome (TS) or Klinefelter syndrome (KS). The ICD-10 inquiry returned originally 134 patients with TS diagnosis. Manual verification of the patient records revealed, however, that 25 of them did not meet the definition for TS (9) and therefore 109 TS patients were included in the analyses. Similarly, we excluded 5 of the 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 85% (n = 68) KS patients. Approximately half of TS (51%) and KS (55%) patients were diagnosed during the study period.

To study the management of bilateral cryptorchidism, we evaluated all 46,XY DSD patients retrieved by the ICD-10 search (Table 1). The patient records of boys referred for isolated bilateral cryptorchidism or a more complex phenotype accompanied by bilaterally undescended testes were reviewed. The age at bilateral orchiopexy or the first of the two unilateral orchiopexies was recorded for each boy and used in subsequent analyses.

Statistical analyses

Correlations between variables were assessed with Spearman rank correlation analysis. Mann–Whitney U test and chi-square test were used to compare the ages of boys with bilateral cryptorchidism operated between 2004 and 2007 or 2008 and 2014. The data in the text are presented with a mean ± s.d. and the data in the tables as median (range) unless otherwise stated. P < 0.05 was accepted to indicate statistical significance.

Results

Phenotypic spectrum of DSD patients and timing of diagnosis

We identified 3206 patients who were evaluated for one or multiple ICD-10 diagnosis of interest in either Pediatric, Pediatric Endocrine and/or Pediatric Surgery Outpatient Clinics at the Helsinki University Hospital between 2004 and 2014. Over two-thirds of these patients (72%) had minor deviations of the genitourinary tract that are not classified as DSDs (Fig. 1 and Table 1). Patients with a DSD diagnosis (n = 550) were divided into three karyotype-based subgroups as suggested in the Chicago consensus statement (1); 53.3% had 46,XY DSD; 37.1% had sex chromosome DSD and 9.6% had 46,XX DSD (Fig. 1). Only 21% of 46,XX DSD patients and 7% of 46,XY DSD patients had a molecular genetic diagnosis, and none of those were made with next-generation sequencing methods. Even in patients with a distinct phenotype, such as persistent Müllerian duct syndrome, the diagnosis was seldom confirmed genetically. Age at diagnosis was available for 75% of 46,XY DSD patients, 86% of 46,XX DSD patients and 87% of sex chromosome DSD patients. Table 2 shows detailed distribution and timing of diagnoses among these DSD patients; most common diagnoses were bilateral cryptorchidism (23.1%), TS (19.8%) and KS (14.5%). The mean age at diagnosis was 2.2 ± 3.8 years for 46,XY DSD, 2.4 ± 4.6 years for 46,XX DSD and 5.3 ± 5.8 years for sex chromosome DSD. In the majority of patients with 46,XY DSD or 46,XX DSD the diagnosis, based on phenotype or molecular genetic finding, was made immediately after birth, apart from 46,XX DSD patients expressing SRY and those presenting DSD as part of a syndrome.

Table 2

Classification of DSD patients (n = 550) by molecular diagnosis or phenotype, age at diagnosis and rate of molecular genetic diagnoses.

n (%) Median (range) age at diagnosis, years Molecular genetic diagnosis (%)
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 duct syndrome) 7 (1.3) 0.7 (0–2.4) 29
(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, vaginal atresia, clitoris hyperplasia) 5 (0.9) 0.05 (0–10.6) 0
 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

Consanguinity was seldom reported in our data: only in two families, the parents were either first or second cousins. Two families with multiple DSD cases were identified. One family presented with several cases of persistent Müllerian duct syndrome. In the other family, there were two brothers with a DSD phenotype of unknown etiology (one brother had a micropenis with proximal hypospadias and a vaginal remnant and the other proximal hypospadias). In addition, three families where the DSD patient’s sibling had a minor anatomic deviation were identified.

We next investigated the annual number of new DSD patients between 2004 and 2014 (n = 290), excluding patients who had been diagnosed before 2004 and had follow-up visits during the survey period. The annual number of new DSD patients remained stable (26 ± 7 patients per year; mean ± s.d., range 10–40) and did not correlate with time (r = 0.18, P = 0.6, n = 11). No significant trends in the annual number of patients were observed either when estimated separately in subgroups of 46,XY DSD (range 5–24, r = 0.31, P = 0.4, n = 11), sex chromosome DSD (range 5–15, r = −0.43, P = 0.18, n = 11) and 46,XX DSD (range 0–6, r = −0.50, P = 0.12, n = 11).

Timing of diagnosis in sex chromosome DSDs: Turner syndrome and Klinefelter syndrome

Our data allowed us to estimate the age at diagnosis of (TS) and (KS) (Fig. 2). For the 80 boys with KS, the diagnosis was set at the mean age of 6.8 ± 6.2 years mostly due to specific language impairment and/or learning difficulties (40%), delayed motor development (13%) or small testicles (11%). Twelve boys were diagnosed already before birth (Fig. 2). Boys referred for evaluation due to developmental issues were aged 8.0 ± 3.5 years, and boys detected due to small testicular size 15.8 ± 1.3 years. Klinefelter boys diagnosed after birth were most frequently referred from the local healthcare center (24%), maternity hospital (9%) or department of pediatric neurology (9%).

Figure 2
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.

Citation: Endocrine Connections 7, 4; 10.1530/EC-18-0070

The girls with TS (n = 109) were diagnosed at the mean age of 4.7 ± 5.5 years. The age distribution was skewed as twenty-five girls were diagnosed prenatally, and, in 47% of the cases, diagnosis was reached by the age of one year (Fig. 2). Turner girls diagnosed after birth were most frequently referred by child health care clinic (19%), maternity hospital (16%) or another hospital district (6%). The main complaint (41% of all cases) was delayed growth. There were no significant trends in the age at diagnosis in either KS or TS patient groups between 2004 and 2014 (KS range 0–17 year, r = 0.05, P = 0.75, n = 44; TS range 0–17 year, r = 0.003, P = 0.98, n = 56).

Figure 3
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.

Citation: Endocrine Connections 7, 4; 10.1530/EC-18-0070

Timing of management in bilateral cryptorchidism

Finally, we reviewed the changes in the management of cryptorchidism by estimating the age at operation for bilateral cryptorchidism before (years 2004–2007) and following the release of the Nordic consensus (years 2008–2014) on treatment of undescended testes (8). Altogether, during the whole study period (2004–2014), 142 patients were operated and the average age of operation for bilateral cryptorchidism was 45.1 ± 44.8 months. The annual number of operated patients (range 8–17) did not increase significantly during the survey period (R = 0.41, P = 0.21, n = 11). However, the age at operation declined after the release of the consensus from 54.5 ± 43.0 months to 41.1 ± 45.3 months (P = 0.0001). Indeed, before the Nordic consensus statement, all bilateral cases (n = 42) were operated after the age of 1 year but after 2007, almost one-third (28 of 100 boys) was operated before the age of 1 year (P = 0.0001, Fig. 3). To exclude boys with acquired cryptorchidism and cases of congenital cryptorchidism missed in early childhood, we limited the analysis to those boys operated before the age of three (23). In this subanalysis, the age at operation had declined from 24.5 ± 5.4 months in boys operated between 2004 and 2007 to 13.7 ± 5.3 months in those operated after 2007 (P < 0.0001).

Discussion

Attempts to estimate the etiological distribution of DSDs according to the 2006-launched DSD classification system are few. In our series, approximately half of the patients had 46,XY DSD, whereas only one-tenth (9.6%) had 46,XX DSD. The proportion of 46,XY DSD patients is similar to the results reported from Turkey (47%) (12), South Africa (57%) (13) and North India (52.5%) (17), and somewhat lower than has been reported from Indonesia (68%) (16). On the other hand, our series contained more cases with sex chromosome DSDs than the previously mentioned reports, which may reflect differences in prenatal screening policies. Of note, in a recent Danish nationwide 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 our study, congenital adrenal hyperplasia (CAH) was expectedly the most common cause of 46,XX DSD. After the implementation of the newborn screening in Finland in 2015, six new CAH patients have been diagnosed by it. We anticipate that screening leads to better diagnostic yield and conceivably better care for this patient group in the future.

Since early diagnosis of DSD is considered important (7, 25, 26), the efficacy of the diagnostic procedures of most frequent patient groups merits evaluation. The mean age at diagnosis of TS patients in our series was 4.7 years, a result similar to the findings reported from the United States and Spain (26, 27). A quarter of our TS patients was diagnosed prenatally, based on the voluntary, combined first trimester screening (a nuchal translucency scan and maternal serum screening followed by a prenatal chromosome test, if necessary). After birth, the most frequent symptom guiding to diagnosis was short stature (41%), the leading clinical cue also in other studies (26, 27). The diagnosis of KS patients in our series was even further delayed, and the diagnosis was typically suspected during childhood due to developmental problems, and during adolescence due to small testicular size. If the frequency of KS was 1/667 male births in our area (28), we could roughly estimate that, between 2004 and 2006, ~20–30% of the boys with KS were diagnosed before the age of 8 years. This low diagnostic yield is in agreement with the Danish data suggesting that only 10% of Danish KS patients are diagnosed before the age of 14 years (29). One possibility to expedite diagnostics would be to include sex chromosome abnormalities in the national newborn screening programs, an idea that has been well-taken by parents of KS patients and pediatricians (10, 30). 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 services required for variable defects in childhood (31). On the other hand, many pregnancies, in which TS is prenatally diagnosed, are currently terminated, although the severity of the TS phenotype is hard to predict and a postnatal re-evaluation of chromosomes is needed for an accurate diagnosis (9, 31).

The timing of orchiopexy is highly variable, and for example, 95% of surgeries were performed after the first year of life in German hospitals (32), and in Singapore, the corresponding number was 70% (33). Nordic guidelines for the treatment of cryptorchidism were renewed at 2007 and accordingly the age for orchiopexy was advanced to 6–12 months (8). We tested whether implementation of the guideline in our tertiary center functions as an indicator for standard of care. Between 2004 and 2007, before the release of the Nordic consensus statement (8), not a single boy with bilateral cryptorchidism was operated before the age of one year in our hospital, whereas thereafter, the age at orchiopexy has decreased at least by 10 months. Our finding is in line with the results published from Sweden and Norway (34, 35).

In this cohort, 21% of patients with 46,XX DSD and only 7% of 46,XY DSD were diagnosed genetically. In the largest patient group of 46,XX DSD, CAH, the current standard of diagnostics is still based on steroid hormone and other biochemical analyses instead of molecular genetics (36). For 46,XY DSD boys, it seems that the etiology remains largely unknown in the clinical setting. In the research setting, however, the overall genetic diagnostic rate achieved with a targeted DSD gene panel, can increase up to 43% (37). An accurate molecular genetic diagnosis is probably valuable in planning the long-term treatment of the patient, although more research is needed to show if the ever more precise diagnostics is associated with beneficial changes in clinical practice from the patient’s perspective (38). While awaiting such evidence, it is still reasonable to conclude that the molecular genetic diagnostic rate should be improved by applying NGS methodology.

Our retrospective study has certain limitations. The ICD-10 classification has multiple different diagnosis codes describing the same phenomenon. To overcome this, we evaluated the patient records and chose the diagnostic code, which best described the patient’s phenotype. Moreover, often there are no specific ICD-10 codes reserved for rare genetic diseases.

Conclusions

We present data from one of the largest series of DSD patients to date. Analysis of patients with chromosomal DSD shows that patients with TS or KS are diagnosed relatively late and often the initiative for the diagnostic workup is related to special needs of the patients (KS) or deceleration of growth (TS). It is feasible that age at diagnosis in patients with TS or KS and the age at operation of bilateral cryptorchidism could serve as indices for monitoring the diagnostic efficiency and management of DSD patients within and between different tertiary centers providing care for this vulnerable patient group.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by the Finnish foundation for Pediatric Research, Academy of Finland and Emil Aaltonen foundation.

Author contribution statement

All authors have provided substantial input to the concept of the study and drafting the article. E K, P M and T R designed the study. E K and A T collected the data. P M, S T, M H and T R advised in interpreting the patient data. E K analyzed the data and wrote the first draft of the manuscript. All authors contributed in revising and editing the manuscript.

Acknowledgements

The authors acknowledge Prof. Jorma Toppari, MD, PhD, for reading and commenting the manuscript.

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    Gies I, Tournaye H & De Schepper J. Attitudes of parents of Klinefelter boys and pediatricians towards neonatal screening and fertility preservation techniques in Klinefelter syndrome. European Journal of Pediatrics 2016 175 399404. (https://doi.org/10.1007/s00431-015-2657-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Lux A, Kropf S, Kleinemeier E, Jürgensen M, Thyen U & DSD Network Working Group. Clinical evaluation study of the German network of disorders of sex development (DSD)/intersexuality: study design, description of the study population, and data quality. BMC Public Health 2009 9 110. (https://doi.org/10.1186/1471-2458-9-110)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Erdoğan S, Kara C, Uçaktürk A & Aydın M. Etiological classification and clinical assessment of children and adolescents with disorders of sex development. Journal of Clinical Research in Pediatric Endocrinology 2011 3 7783. (http://doi.org/10.4274/jcrpe.v3i2.16)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Ganie Y, Aldous C, Balakrishna Y & Wiersma R. Disorders of sex development in children in KwaZulu-Natal Durban South Africa: 20-year experience in a tertiary centre. Journal of Pediatric Endocrinology and Metabolism 2016 30 1118. (https://doi.org/10.1515/jpem-2016-0152)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Jaruratanasirikul S & Engchaun V. Management of children with disorders of sex development: 20-year experience in southern Thailand. World Journal of Pediatrics 2014 10 168174. (https://doi.org/10.1007/s12519-013-0418-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Al-Jurayyan NAM. Ambiguous genitalia: two decades of experience. Annals of Saudi Medicine 2011 31 284288. (https://doi.org/10.4103/0256-4947.81544)

  • 16

    Juniarto AZ, van der Zwan YG, Santosa A, Ariani MD, Eggers S, Hersmus R, Themmen AP, Bruggenwirth HT, Wolffenbuttel KP, Sinclair A, et al. Hormonal evaluation in relation to phenotype and genotype in 286 patients with a disorder of sex development from Indonesia. Clinical Endocrinology 2016 85 247257. (https://doi.org/10.1111/cen.13051)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Walia R, Singla M, Vaiphei K, Kumar S & Bhansali A. Disorders of sex development: a study of 194 cases. Endocrine Connections 2018 7 364371. (https://doi.org/10.1530/EC-18-0022)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Hiort O, Wünsch L, Cools M, Looijenga L & Cuckow P. Requirements for a multicentric multidisciplinary registry on patients with disorders of sex development. Journal of Pediatric Urology 2012 8 624628. (https://doi.org/10.1016/j.jpurol.2012.09.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Pasterski V, Prentice P & Hughes IA. Consequences of the Chicago consensus on disorders of sex development (DSD): current practices in Europe. Archives of Disease in Childhood 2010 95 618623. (https://doi.org/10.1136/adc.2009.163840)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Creighton S, Chernausek SD, Romao R, Ransley P & Salle JP. Timing and nature of reconstructive surgery for disorders of sex development – introduction. Journal of Pediatric Urology 2012 8 602610. (https://doi.org/10.1016/j.jpurol.2012.10.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Official Statistics of Finland. Population: Population structure. Helsinki, Finland: Statistics Finland, 2017. (available at: http://www.stat.fi/til/vaerak/index_en.html)

    • PubMed
    • Export Citation
  • 22

    Bonomi M, Rochira V, Pasquali D, Balercia G, Jannini EA, Ferlin A. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. Journal of Endocrinological Investigation 2016 40 123134. (https://doi.org/10.1007/s40618-016-0541-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Wohlfahrt-Veje C, Boisen KA, Boas M, Damgaard IN, Kai CM, Schmidt IM, Chellakooty M, Suomi AM, Toppari J, Skakkebaek NE, et al. Acquired cryptorchidism is frequent in infancy and childhood. International Journal of Andrology 2009 32 423428. (https://doi.org/10.1111/j.1365-2605.2008.00946.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Berglund A, Johannsen TH, Stochholm K, Viuff MH, Fedder J, Main KM, Gravholt CH. Incidence, prevalence, diagnostic delay, and clinical presentation of female 46,XY disorders of sex development. Journal of Clinical Endocrinology and Metabolism 2016 101 45324540. (https://doi.org/10.1210/jc.2016-2248)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Hersmus R, Stoop H, White SJ, Drop SLS, Oosterhuis JW, Incrocci L, Wolffenbuttel KP, Looijenga LHJ. Delayed recognition of disorders of sex development (DSD): a missed opportunity for early diagnosis of malignant germ cell tumors. International Journal of Endocrinology 2012 2012 671209.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Sävendahl L & Davenport ML. Delayed diagnoses of Turner’s syndrome: proposed guidelines for change. Journal of Pediatrics 2000 137 455459. (https://doi.org/10.1067/mpd.2000.107390)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Ríos Orbañanos I, Vela Desojo A, Martinez-Indart L, Grau Bolado G, Rodriguez Estevez A & Rica Echevarria I. Turner syndrome: from birth to adulthood. Endocrinología y Nutrición 2015 62 499506. (https://doi.org/10.1016/j.endonu.2015.06.010)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Bojesen A, Juul S & Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. Journal of Clinical Endocrinology and Metabolism 2003 88 622626. (https://doi.org/10.1210/jc.2002-021491)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Groth KA, Skakkebæk A, Høst C, Gravholt CH & Bojesen A. Clinical review: Klinefelter syndrome – a clinical update. Journal of Clinical Endocrinology and Metabolism 2013 98 2030. (https://doi.org/10.1210/jc.2012-2382)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Herlihy AS & McLachlan RI. Screening for Klinefelter syndrome. Current Opinion in Endocrinology, Diabetes and Obesity 2015 22 224229. (https://doi.org/10.1097/MED.0000000000000154)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Baena N, De Vigan C, Cariati E, Clementi M, Stoll C, Caballín MR, Guitart M. Turner syndrome: evaluation of prenatal diagnosis in 19 European registries. American Journal of Medical Genetics Part A 2004 129A 1620. (https://doi.org/10.1002/ajmg.a.30092)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Hensel KO, Caspers T, Jenke AC, Schuler E & Wirth S. Operative management of cryptorchidism: guidelines and reality – a 10-year observational analysis of 3587 cases. BMC Pediatrics 2015 15 116. (https://doi.org/10.1186/s12887-015-0429-1)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Nah SA, Yeo CSW, How GY, Allen JC, Lakshmi NK, Yap T-L, Jacobsen AS, Low Y, Ong CC. Undescended testis: 513 patients’ characteristics, age at orchidopexy and patterns of referral. Archives of Disease in Childhood 2014 99 401406. (https://doi.org/10.1136/archdischild-2013-305225)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Bergbrant S, Omling E, Björk J & Hagander L. Cryptorchidism in Sweden: a nationwide study of prevalence, operative management, and complications. Journal of Pediatrics 2018 194 197203.e6. (https://doi.org/10.1016/j.jpeds.2017.09.062)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Nilsson R, Omland H, Dahl AA & Johansen TEB. Early outcome of orchiopexy and analysis of predictive factors: a retrospective study from 2001 to 2010 in a Norwegian regional hospital. Scandinavian Journal of Urology 2014 48 474481. (https://doi.org/10.3109/21681805.2014.905631)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Kulle A, Krone N, Holterhus PM, Schuler G, Greaves RF, Juul A, de Rijke YB, Hartmann MF, Saba A, Hiort O, et al. Steroid hormone analysis in diagnosis and treatment of DSD: position paper of EU COST Action BM 1303 'DSDnet'. European Journal of Endocrinology 2017 176 P1P9. (https://doi.org/10.1530/EJE-16-0953)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T, Hewitt J, Lambeth L, Bouty A, Knarston IM, Tan TY, et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biology 2016 17 243. (https://doi.org/10.1186/s13059-016-1105-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Alhomaidah D, McGowan R & Ahmed SF. The current state of diagnostic genetics for conditions affecting sex development. Clinical Genetics 2017 91 157162. (https://doi.org/10.1111/cge.12912)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • 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).

  • 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.

  • 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.

  • 1

    Hughes IA, Houk C, Ahmed SF & Lee PA. Consensus statement on management of intersex disorders. Journal of Pediatric Urology 2006 2 148162. (https://doi.org/10.1016/j.jpurol.2006.03.004)

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  • 2

    Hutson JM, Grover SR, O’Connell M & Pennell SD. Malformation syndromes associated with disorders of sex development. Nature Reviews Endocrinology 2014 10 476487. (https://doi.org/10.1038/nrendo.2014.83)

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  • 3

    Bonde JP, Flachs EM, Rimborg S, Glazer CH, Giwercman A, Ramlau-Hansen CH, Hougaard KS, Høyer BB, Hærvig KK, Petersen SB, et al. The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis. Human Reproduction Update 2016 23 104125. (https://doi.org/10.1093/humupd/dmw036)

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  • 4

    Ahmed SF, Achermann JC, Arlt W, Balen A, Conway G, Edwards Z, Elford S, Hughes IA, Izatt L, Krone N, et al. Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015). Clinical Endocrinology 2015 84 771788. (https://doi.org/10.1111/cen.12857)

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  • 5

    Nordenström A, Röhle R, Thyen U, Bouvattier C, Slowikowska-Hilczer J, Reisch N, et al. Hormone therapy and patient satisfaction with treatment, in a large cohort of diverse disorders of sex development. Clinical Endocrinology 2018 88 397408. (https://doi.org/10.1111/cen.13518)

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  • 6

    Quinton R, Mamoojee Y, Jayasena CN, Young J, Howard S, Dunkel L, Cheetham T, Smith N, Dwyer AA. Society for Endocrinology UK guidance on the evaluation of suspected disorders of sexual development: emphasising the opportunity to predict adolescent pubertal-failure through a neonatal diagnosis of absent mini-puberty. Clinical Endocrinology 2016 86 305306. (https://doi.org/10.1111/cen.13257)

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  • 7

    Cassia Amaral R, Inacio M, Brito VN, Bachega TASS, Oliveira AA, Domenice S, Denes FT, Sircili MH, Arnhold IJ, Madureira G, et al. Quality of life in a large cohort of adult Brazilian patients with 46,XX and 46,XY disorders of sex development from a single tertiary centre. Clinical Endocrinology 2015 82 274279. (https://doi.org/10.1111/cen.12572)

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  • 8

    Ritzén EM, Bergh A, Bjerknes R, Christiansen P, Cortes D, Haugen SE, Jörgensen N, Kollin C, Lindahl S, Läckgren G, et al. Nordic consensus on treatment of undescended testes. Acta Paediatrica 2007 96 638643. (https://doi.org/10.1111/j.1651-2227.2006.00159.x)

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    Bondy CA & Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. Journal of Clinical Endocrinology and Metabolism 2007 92 1025. (https://doi.org/10.1210/jc.2006-1374)

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  • 10

    Gies I, Tournaye H & De Schepper J. Attitudes of parents of Klinefelter boys and pediatricians towards neonatal screening and fertility preservation techniques in Klinefelter syndrome. European Journal of Pediatrics 2016 175 399404. (https://doi.org/10.1007/s00431-015-2657-7)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Lux A, Kropf S, Kleinemeier E, Jürgensen M, Thyen U & DSD Network Working Group. Clinical evaluation study of the German network of disorders of sex development (DSD)/intersexuality: study design, description of the study population, and data quality. BMC Public Health 2009 9 110. (https://doi.org/10.1186/1471-2458-9-110)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Erdoğan S, Kara C, Uçaktürk A & Aydın M. Etiological classification and clinical assessment of children and adolescents with disorders of sex development. Journal of Clinical Research in Pediatric Endocrinology 2011 3 7783. (http://doi.org/10.4274/jcrpe.v3i2.16)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Ganie Y, Aldous C, Balakrishna Y & Wiersma R. Disorders of sex development in children in KwaZulu-Natal Durban South Africa: 20-year experience in a tertiary centre. Journal of Pediatric Endocrinology and Metabolism 2016 30 1118. (https://doi.org/10.1515/jpem-2016-0152)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Jaruratanasirikul S & Engchaun V. Management of children with disorders of sex development: 20-year experience in southern Thailand. World Journal of Pediatrics 2014 10 168174. (https://doi.org/10.1007/s12519-013-0418-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Al-Jurayyan NAM. Ambiguous genitalia: two decades of experience. Annals of Saudi Medicine 2011 31 284288. (https://doi.org/10.4103/0256-4947.81544)

  • 16

    Juniarto AZ, van der Zwan YG, Santosa A, Ariani MD, Eggers S, Hersmus R, Themmen AP, Bruggenwirth HT, Wolffenbuttel KP, Sinclair A, et al. Hormonal evaluation in relation to phenotype and genotype in 286 patients with a disorder of sex development from Indonesia. Clinical Endocrinology 2016 85 247257. (https://doi.org/10.1111/cen.13051)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Walia R, Singla M, Vaiphei K, Kumar S & Bhansali A. Disorders of sex development: a study of 194 cases. Endocrine Connections 2018 7 364371. (https://doi.org/10.1530/EC-18-0022)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Hiort O, Wünsch L, Cools M, Looijenga L & Cuckow P. Requirements for a multicentric multidisciplinary registry on patients with disorders of sex development. Journal of Pediatric Urology 2012 8 624628. (https://doi.org/10.1016/j.jpurol.2012.09.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Pasterski V, Prentice P & Hughes IA. Consequences of the Chicago consensus on disorders of sex development (DSD): current practices in Europe. Archives of Disease in Childhood 2010 95 618623. (https://doi.org/10.1136/adc.2009.163840)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Creighton S, Chernausek SD, Romao R, Ransley P & Salle JP. Timing and nature of reconstructive surgery for disorders of sex development – introduction. Journal of Pediatric Urology 2012 8 602610. (https://doi.org/10.1016/j.jpurol.2012.10.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Official Statistics of Finland. Population: Population structure. Helsinki, Finland: Statistics Finland, 2017. (available at: http://www.stat.fi/til/vaerak/index_en.html)

    • PubMed
    • Export Citation
  • 22

    Bonomi M, Rochira V, Pasquali D, Balercia G, Jannini EA, Ferlin A. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. Journal of Endocrinological Investigation 2016 40 123134. (https://doi.org/10.1007/s40618-016-0541-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Wohlfahrt-Veje C, Boisen KA, Boas M, Damgaard IN, Kai CM, Schmidt IM, Chellakooty M, Suomi AM, Toppari J, Skakkebaek NE, et al. Acquired cryptorchidism is frequent in infancy and childhood. International Journal of Andrology 2009 32 423428. (https://doi.org/10.1111/j.1365-2605.2008.00946.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Berglund A, Johannsen TH, Stochholm K, Viuff MH, Fedder J, Main KM, Gravholt CH. Incidence, prevalence, diagnostic delay, and clinical presentation of female 46,XY disorders of sex development. Journal of Clinical Endocrinology and Metabolism 2016 101 45324540. (https://doi.org/10.1210/jc.2016-2248)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Hersmus R, Stoop H, White SJ, Drop SLS, Oosterhuis JW, Incrocci L, Wolffenbuttel KP, Looijenga LHJ. Delayed recognition of disorders of sex development (DSD): a missed opportunity for early diagnosis of malignant germ cell tumors. International Journal of Endocrinology 2012 2012 671209.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Sävendahl L & Davenport ML. Delayed diagnoses of Turner’s syndrome: proposed guidelines for change. Journal of Pediatrics 2000 137 455459. (https://doi.org/10.1067/mpd.2000.107390)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Ríos Orbañanos I, Vela Desojo A, Martinez-Indart L, Grau Bolado G, Rodriguez Estevez A & Rica Echevarria I. Turner syndrome: from birth to adulthood. Endocrinología y Nutrición 2015 62 499506. (https://doi.org/10.1016/j.endonu.2015.06.010)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Bojesen A, Juul S & Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. Journal of Clinical Endocrinology and Metabolism 2003 88 622626. (https://doi.org/10.1210/jc.2002-021491)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Groth KA, Skakkebæk A, Høst C, Gravholt CH & Bojesen A. Clinical review: Klinefelter syndrome – a clinical update. Journal of Clinical Endocrinology and Metabolism 2013 98 2030. (https://doi.org/10.1210/jc.2012-2382)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Herlihy AS & McLachlan RI. Screening for Klinefelter syndrome. Current Opinion in Endocrinology, Diabetes and Obesity 2015 22 224229. (https://doi.org/10.1097/MED.0000000000000154)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Baena N, De Vigan C, Cariati E, Clementi M, Stoll C, Caballín MR, Guitart M. Turner syndrome: evaluation of prenatal diagnosis in 19 European registries. American Journal of Medical Genetics Part A 2004 129A 1620. (https://doi.org/10.1002/ajmg.a.30092)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Hensel KO, Caspers T, Jenke AC, Schuler E & Wirth S. Operative management of cryptorchidism: guidelines and reality – a 10-year observational analysis of 3587 cases. BMC Pediatrics 2015 15 116. (https://doi.org/10.1186/s12887-015-0429-1)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Nah SA, Yeo CSW, How GY, Allen JC, Lakshmi NK, Yap T-L, Jacobsen AS, Low Y, Ong CC. Undescended testis: 513 patients’ characteristics, age at orchidopexy and patterns of referral. Archives of Disease in Childhood 2014 99 401406. (https://doi.org/10.1136/archdischild-2013-305225)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Bergbrant S, Omling E, Björk J & Hagander L. Cryptorchidism in Sweden: a nationwide study of prevalence, operative management, and complications. Journal of Pediatrics 2018 194 197203.e6. (https://doi.org/10.1016/j.jpeds.2017.09.062)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Nilsson R, Omland H, Dahl AA & Johansen TEB. Early outcome of orchiopexy and analysis of predictive factors: a retrospective study from 2001 to 2010 in a Norwegian regional hospital. Scandinavian Journal of Urology 2014 48 474481. (https://doi.org/10.3109/21681805.2014.905631)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Kulle A, Krone N, Holterhus PM, Schuler G, Greaves RF, Juul A, de Rijke YB, Hartmann MF, Saba A, Hiort O, et al. Steroid hormone analysis in diagnosis and treatment of DSD: position paper of EU COST Action BM 1303 'DSDnet'. European Journal of Endocrinology 2017 176 P1P9. (https://doi.org/10.1530/EJE-16-0953)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T, Hewitt J, Lambeth L, Bouty A, Knarston IM, Tan TY, et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biology 2016 17 243. (https://doi.org/10.1186/s13059-016-1105-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Alhomaidah D, McGowan R & Ahmed SF. The current state of diagnostic genetics for conditions affecting sex development. Clinical Genetics 2017 91 157162. (https://doi.org/10.1111/cge.12912)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation