Standardised data collection for clinical follow-up and assessment of outcomes in differences of sex development (DSD): recommendations from the COST action DSDnet

in European Journal of Endocrinology
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  • 1 Paediatric Endocrinology and Diabetology, Department of Paediatrics and Department of BioMedical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  • | 2 Paediatric Endocrinology Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  • | 3 Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, UK
  • | 4 Department of Obstetrics and Gynaecology, Ramazzini Hospital, AUSL Modena, Modena, Italy
  • | 5 CAH Support Group, UK
  • | 6 Department of Paediatric Endocrinology, Charité University Medicine, Humboldt University Berlin, Berlin, Germany (recently deceased)
  • | 7 Department of Psychology, University of Cambridge, Cambridge, UK
  • | 8 Clinical Center of Endocrinology and Gerontology, Medical University-Sofia, Medical Faculty, Sofia, Bulgaria
  • | 9 Institute for Sex Research and Forensic Psychiatry, University Clinic Hamburg Eppendorf, Hamburg, Germany
  • | 10 Department of Paediatric Surgery, Medical University Vienna, Vienna, Austria
  • | 11 DSDNederland, The Netherlands
  • | 12 Division of Paediatric Endocrinology and Diabetes, Department of Paediatric and Adolescent Medicine, University of Lübeck, Lübeck, Germany
  • | 13 Department of Paediatric Endocrinology, Ghent University Hospital, Department of Internal Medicine and Paediatrics, University of Ghent, Ghent, Belgium

Correspondence should be addressed to M Cools E-mail martine.cools@ugent.be

*(C Flück and A Nordenström contributed equally to this work)

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The treatment and care of individuals who have a difference of sex development (DSD) have been revised over the past two decades and new guidelines have been published. In order to study the impact of treatments and new forms of management in these rare and heterogeneous conditions, standardised assessment procedures across centres are needed. Diagnostic work-up and detailed genital phenotyping are crucial at first assessment. DSDs may affect general health, have associated features or lead to comorbidities which may only be observed through lifelong follow-up. The impact of medical treatments and surgical (non-) interventions warrants special attention in the context of critical review of current and future care. It is equally important to explore gender development early and refer to specialised services if needed. DSDs and the medical, psychological, cultural and familial ways of dealing with it may affect self-perception, self-esteem, and psychosexual function. Therefore, psychosocial support has become one of the cornerstones in the multidisciplinary management of DSD, but its impact remains to be assessed. Careful clinical evaluation and pooled data reporting in a global DSD registry will allow linking genetic, metabolomic, phenotypic and psychological data. For this purpose, our group of clinical experts and patient and parent representatives designed a template for structured longitudinal follow-up. In this paper, we explain the rationale behind the selection of the dataset. This tool provides guidance to professionals caring for individuals with a DSD and their families. At the same time, it collects the data needed for answering unsolved questions of patients, clinicians, and researchers. Ultimately, outcomes for defined subgroups of rare DSD conditions should be studied through large collaborative endeavours using a common protocol.

Abstract

The treatment and care of individuals who have a difference of sex development (DSD) have been revised over the past two decades and new guidelines have been published. In order to study the impact of treatments and new forms of management in these rare and heterogeneous conditions, standardised assessment procedures across centres are needed. Diagnostic work-up and detailed genital phenotyping are crucial at first assessment. DSDs may affect general health, have associated features or lead to comorbidities which may only be observed through lifelong follow-up. The impact of medical treatments and surgical (non-) interventions warrants special attention in the context of critical review of current and future care. It is equally important to explore gender development early and refer to specialised services if needed. DSDs and the medical, psychological, cultural and familial ways of dealing with it may affect self-perception, self-esteem, and psychosexual function. Therefore, psychosocial support has become one of the cornerstones in the multidisciplinary management of DSD, but its impact remains to be assessed. Careful clinical evaluation and pooled data reporting in a global DSD registry will allow linking genetic, metabolomic, phenotypic and psychological data. For this purpose, our group of clinical experts and patient and parent representatives designed a template for structured longitudinal follow-up. In this paper, we explain the rationale behind the selection of the dataset. This tool provides guidance to professionals caring for individuals with a DSD and their families. At the same time, it collects the data needed for answering unsolved questions of patients, clinicians, and researchers. Ultimately, outcomes for defined subgroups of rare DSD conditions should be studied through large collaborative endeavours using a common protocol.

Introduction

The term differences (disorders) of sex development (DSD) refers to a heterogeneous group of conditions that affect the urogenital tract and result in atypical sex development. The prevalence of the individual conditions is mostly very low and only a small fraction of all conditions characterised by variations in sex characteristics pose major clinical challenges and/or require multidisciplinary care (1). Recent outcome studies suggest that having a DSD may impact an individuals’ health status and psychological well-being in every stage of life (2, 3, 4), though physical or psychological comorbidities have been rarely studied in detail, especially in adults. Influencing factors include the rarity of the respective conditions, individual drawbacks to participate in medical studies and the dispersion of affected individuals over decentralised health care structures, with frequent loss of patients for follow-up. In addition, the quality of care for individuals with a DSD varies considerably across Europe, between centres and within diagnostic groups. Patient satisfaction with care is lowest amongst individuals with the rarest conditions (5).

The development of a concrete and evidence-based protocol for structured review and clinical data collection in children and adults who have a DSD, at various age intervals, may be pivotal in addressing these difficulties (6) (Fig. 1). It minimises bias in clinical assessments and can provide guidance to clinicians who do not regularly see these patients. In fact, there is a need to support health care professionals in assessing a small amount of data regularly as part of a holistic routine clinical care. Equally important, it enables exchange of data amongst clinical centres and in research networks such as the international DSD Registry I-DSD (https://www.i-dsd.org), allowing large-scale multicentre studies. For patients, it can increase understanding of their condition, provide clarity about one’s future medical needs, enhance compliance and facilitate discussions with caregivers (7). From a healthcare point of view, adherence to an evidence-based assessment protocol can serve as a quality indicator and benchmarking tool (8).

Figure 1
Figure 1

Schema of the longitudinal I-DSD registration tool showing time points, ages for data entry, starting at the age of diagnosis. Neonatal data, including genetic information if available, should always be entered regardless of the age at diagnosis.

Citation: European Journal of Endocrinology 181, 5; 10.1530/EJE-19-0363

Several aspects of DSD management are surrounded by controversy or uncertainty and have led to a thorough revision of clinical practice in recent years (1). For example, genital surgery in young children is more often avoided nowadays in order to protect childrens’ rights of an open future and integrity of the body; and increasing numbers of children grow up with atypical-looking genitalia, of which the psychological impact is not known (9). Many DSD teams provide psychological support to affected families as a standard component of care nowadays, children are informed early about their condition, and gender issues are openly discussed (6). Some teams include peer support in the medical management plan (10). Structured longitudinal assessment of individuals with a DSD across centres may provide future evidence in favour or against these new practices, with specific relevance to (rare) individual diagnoses, provided that all relevant parameters are considered in parallel and by standardised measurement tools.

In accordance with patient aspirations, the promotion of a standardised protocol that uses a non-binary vocabulary and medical approach can be paramount in inducing societal change as well as amongst the medical community, in attitudes towards gender perception and normative paradigms of sex, including genital characteristics (11). This will by itself be instrumental in defining the place, timing and the specific medical need of genital surgery.

Development of consensus on standardised data collection

The development of a meaningful, holistic schedule for clinical assessment that allows for standardised longitudinal data collection over time in individuals who have a DSD has been the primary goal of an expert multidisciplinary working group, including representatives from patient support groups. This group operated in the period 2013–2017 in the framework of the European Cooperation in Science and Technology (COST) Action BM1303 “DSDnet” (www.DSDnet.eu), funded by the European Union Horizon 2020 programme. Collaboratively, the group (1) reviewed the literature on existing instruments for clinical phenotyping at all ages; (2) defined their major strengths and shortcomings as well as hitherto insufficiently covered areas of (para)medical attention; and (3) discussed essential characteristics of a qualitative longitudinal follow-up programme until agreement was reached on a protocol for standardised assessment at various ages that was versatile enough to be used in clinical settings as well as within electronic global platforms such as the I-DSD Registry.

General dataset and ages at which follow-up assessments are recommended

Criteria for referral of a child for expert evaluation are specified in the UK guidelines (12). At first referral, linking the case to original health records and obtaining consent for sharing data (local, national, international) are crucial. Basic DSD-related information, such as diagnosis, karyotype, birth-assigned sex, and social gender should also be included (Table 1). Thereafter, appropriate time intervals for clinical revision of patients depend on the respective conditions, patient age, and individual circumstances. However, for registration and research purposes, it was considered crucial to standardise a minimal set of time points, corresponding to important developmental milestones, at which relevant clinical data should be collected (Fig. 1).

Table 1

Neonatal assessment (within first month of birth).

Parameters

Units/ options

Parameters

Units/ options

GeneralSurgery
 Date of Assessmentdd/mm/yyyy Left Gonad BiopsyYes/ No/ Not known
 Age at Assessmentyears Right Gonad BiopsyYes/ No/ Not known
 Gestational Ageweeks Left GonadectomyYes/ No/ Not known
 Birth Weightg Right GonadectomyYes/ No/ Not known
 Birth Lengthcm Genital reconstructive surgery**None/ clitoral surgery / vaginal surgery / labioscrotal surgery / hypospadias surgery / urethral surgery other than hypospadias; age
 Birth Head Circumferencecm Reasons for genital reconstructive surgeryFunctional / cosmesis / both
 Weightkg Post Surgical ComplicationsYes/ No/ Not known; if yes, describe.
 HeightcmPsychosocial
 BMIkg/m2 Change in Legal SexYes/ No/ Not known
 Mothers Heightcm Psychosocial Support Offered to ParentsYes/ No/ Not known
 Fathers Heightcm Ongoing Psychosocial SupportYes/ No/ Not known
 Mid Parental Heightcm
 Original Sex AssignedMale/ Female/ Both/ Not assigned/ OtherMedication
 Current GenderMale/ Female/ Both/ Not assigned/ Other TestosteroneYes (IM, Oral, Transdermal)/ No/ Not known
 Child raised asMale/ Female/ Both / Other OestrogenYes (IM, Oral, Transdermal)/ No/ Not known
 Associated Conditions* DHTYes (IM, Oral, Transdermal)/ No/ Not known
 Known SyndromeYes/ No Aromatase InhibitorYes/ No/ Not known
External Phenotype GnRH analoguesYes/ No/ Not known
 MeatusTypical female/ Perineal/ Scrotal/ Penoscrotal/ Penile/ Coronal/ Typical male GlucocorticoidsYes/ No/ Not known
 Left Gonad LocationImpalpable/ Inguinal/ Inguinoscrotal/ Labioscrotal FludrocortisoneYes/ No/ Not known
 Right Gonad LocationImpalpable/ Inguinal/ Inguinoscrotal/ Labioscrotal Other drugsYes/ No/ Not known
 Genital Tubercle Length <10/ 10-20/ 21-25/ 26-30/ >30 mmLab Tests
 Phallus SizeWithin/ Below/ Above the reference range for male; Within/ Below/ Above the reference range for female LHLow/ Normal/ High/ Not known
 Labioscrotal FusionYes/ No FSHLow/ Normal/ High/ Not known
 Anogenital Distance 1# (AGD1)mm AMHLow/ Normal/ High/ Not known
 Anogenital Distance 2## (AGD2),mm Inhibin BLow/ Normal/ High/ Not known
 External Masculinisation Score (EMS) AndrostenedioneLow/ Normal/ High/ Not known
 External Genitalia Score (EGS) Total TestosteroneLow/ Normal/ High/ Not known
Internal Phenotype Free TestosteroneLow/ Normal/ High/ Not known
 Imaging Modality- Left GonadUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy DihydrotestosteroneLow/ Normal/ High/ Not known
 Imaging Modality- Right GonadUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy OestradiolLow/ Normal/ High/ Not known
 Left Gonad MorphologyAbsent/ Streak/ Testis/ Ovary/ Ovotestis/ Other 17-OHPLow/ Normal/ High/ Not known
 Right Gonad MorphologyAbsent/ Streak/ Testis/ Ovary/ Ovotestis/ Other Urine steroidsNormal/ Abnormal
 Imaging Modality- UterusUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy hCG Stimulation TestSpecify protocol
 Uterus MorphologyAbsent/ Müllerian remnants/ rudimentary/ Normal/ Not known Adrenal Stimulation TestSpecify protocol
 Imaging Modality- Left Fallopian TubeUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy 11-deoxycortisolLow/ Normal/ High/ Not known
 Imaging Modality- Right Fallopian TubeUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy PregnenoloneLow/ Normal/ High/ Not known
 Left Fallopian Tube MorphologyAbsent/ Rudimentary/ Normal/ Not known 17-OH PregnenoloneLow/ Normal/ High/ Not known
 Right Fallopian Tube MorphologyAbsent/ Rudimentary/ Normal/ Not known DHEALow/ Normal/ High/ Not known
 Distance- Vaginal Confluence to Bladder Neckcm
 Distance- Vaginal Confluence to Introituscm
 Imaging Modality- Left Vas DeferensUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy
 Imaging Modality- Right Vas DeferensUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy
 Left Vas Deferens MorphologyAbsent/ Rudimentary/ Normal/ Not known
 Right Vas Deferens MorphologyAbsent/ Rudimentary/ Normal/ Not known

*Associated conditions: CNS, heart, renal, skeletal, skin, ENT, eyes, blood and lymph, craniofacial, adrenal, GI tract, haematological, respiratory, SGA (small for gestational age), short stature, non-defined syndrome, other. **Genital reconstructive surgery field may be repeated.

# AGD 1: Distance from the centre of the anus to the posterior base of the labioscrotal folds; ##AGD 2: Distance from the centre of the anus to the anterior base of the phallus.

A summary of neonatal data, where available, should be collected in all cases with later presentation (Table 2). Clinical revision at age 4 years (Table 3) allows for comprehensive assessment of psychological developmental milestones, associated symptoms, and growth patterns, including catch-up growth. The process of informing the child about the condition should start as soon as possible after diagnosis, along with the provision of support in acquiring a vocabulary to talk about the DSD (13). Practical advice on this matter can be found at support group resources (e.g. www.dsdfamilies.org or https://www.iglyo.com/wp-content/uploads/2018/10/Supporting-Your-Intersex-Child.pdf). At age 8 years (Table 3), relevant information on growth and development shortly before start of puberty can be obtained. At this age the child understands more complex information about how the body functions and about the specific DSD. Gender identity or eventual dysphoria may be ascertained and children experiencing uncertainty can be referred for expert psychological or psychiatric evaluation and support. Pubertal development and progression (Table 4) may be compromised in many children who have a DSD. Some children may need hormonal induction of puberty. Standardised assessment at the start of puberty and the outcome of pubertal development are therefore paramount to document, though most children will need clinical revision more frequently. Transition to adult healthcare should be discussed early on during this period (8, 14).

Table 2

Clinical assessment (at any age if first assessment after 1 month of age).

Parameters

Units/ options

Parameters

Units/ options

GeneralSurgery
 Date of Assessmentdd/mm/yyyy Left Gonad BiopsyYes/ No/ Not known
 Age at Assessmentyears Right Gonad BiopsyYes/ No/ Not known
 Gestational Ageweeks Left GonadectomyYes/ No/ Not known
 Birth Weightg Right GonadectomyYes/ No/ Not known
 Birth Lengthcm Genital reconstructive surgery**None/ clitoral surgery / vaginal surgery / labioscrotal surgery / hypospadias surgery / urethral surgery other than hypospadias; age
 Birth Head Circumferencecm Reasons for genital reconstructive surgeryFunctional / cosmesis / both
 Weightkg Post Surgical ComplicationsYes/ No/ Not known; if yes, describe.
 HeightcmPsychosocial
 BMIkg/m2 Change in Legal SexYes/ No/ Not known
 Mothers Heightcm Psychosocial Support Offered to ParentsYes/ No/ Not known
 Fathers Heightcm Ongoing Psychosocial SupportYes/ No/ Not known
 Mid parental heightcm
 Original Sex AssignedMale/ Female/ Both/ Not assigned/ OtherMedication
 Current GenderMale/ Female/ Both/ Not assigned/ Other TestosteroneYes (IM, Oral, Transdermal)/ No/ Not known
 Child raised asMale/ Female/ Both / Other OestrogenYes (IM, Oral, Transdermal)/ No/ Not known
 Associated Conditions* DHTYes (IM, Oral, Transdermal)/ No/ Not known
 Known SyndromeYes/ No Aromatase InhibitorYes/ No/ Not known
External Phenotype GnRH analoguesYes/ No/ Not known
 MeatusTypical female/ Perineal/ Scrotal/ Penoscrotal/ Penile/ Coronal/ Typical male GlucocorticoidsYes/ No/ Not known
 Left Gonad LocationImpalpable/ Inguinal/ Inguinoscrotal/ Labioscrotal FludrocortisoneYes/ No/ Not known
 Right Gonad LocationImpalpable/ Inguinal/ Inguinoscrotal/ Labioscrotal Other drugsYes/ No/ Not known
 Genital Tubercle Length <10/ 10-20/ 21-25/ 26-30/ >30 mmLab Tests
 Phallus SizeWithin/ Below/ Above the reference range for male; Within/ Below/ Above the reference range for female LHLow/ Normal/ High/ Not known
 Labioscrotal FusionYes/ No FSHLow/ Normal/ High/ Not known
 Anogenital Distance 1# (AGD1)mm AMHLow/ Normal/ High/ Not known
 Anogenital Distance 2## (AGD2),mm Inhibin BLow/ Normal/ High/ Not known
 External Masculinisation Score (EMS) AndrostenedioneLow/ Normal/ High/ Not known
 External Genitalia Score (EGS) Total TestosteroneLow/ Normal/ High/ Not known
Internal Phenotype Free TestosteroneLow/ Normal/ High/ Not known
 Imaging Modality- Left GonadUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy DihydrotestosteroneLow/ Normal/ High/ Not known
 Imaging Modality- Right GonadUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy OestradiolLow/ Normal/ High/ Not known
 Left Gonad MorphologyAbsent/ Streak/ Testis/ Ovary/ Ovotestis/ Other 17-OHPLow/ Normal/ High/ Not known
 Right Gonad MorphologyAbsent/ Streak/ Testis/ Ovary/ Ovotestis/ Other Urine steroidsNormal/ Abnormal
 Imaging Modality- UterusUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy hCG Stimulation TestSpecify protocol
 Uterus MorphologyAbsent/ Müllerian remnants/ rudimentary/ Normal/ Not known Adrenal Stimulation TestSpecify protocol
 Imaging Modality- Left Fallopian TubeUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy 11-deoxycortisolLow/ Normal/ High/ Not known
 Imaging Modality- Right Fallopian TubeUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy PregnenoloneLow/ Normal/ High/ Not known
 Left Fallopian Tube MorphologyAbsent/ Rudimentary/ Normal/ Not known 17-OH PregnenoloneLow/ Normal/ High/ Not known
 Right Fallopian Tube MorphologyAbsent/ Rudimentary/ Normal/ Not known DHEALow/ Normal/ High/ Not known
 Distance- Vaginal Confluence to Bladder Neckcm
 Distance- Vaginal Confluence to Introituscm
 Imaging Modality- Left Vas DeferensUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy
 Imaging Modality- Right Vas DeferensUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy
 Left Vas Deferens MorphologyAbsent/ Rudimentary/ Normal/ Not known
 Right Vas Deferens MorphologyAbsent/ Rudimentary/ Normal/ Not known

*Associated conditions: CNS, Heart, Renal, Skeletal, Skin, ENT, Eyes, Blood and Lymp, Craniofacial, Adrenal, GI Tract, Haematological, Respiratory, SGA (Small for Gestational Age), Short stature, Non-defined syndrome, Other. **Genital reconstructive surgery field may be repeated.

#AGD 1: Distance from the centre of the anus to the posterior base of the labioscrotal folds; ##AGD 2: Distance from the centre of the anus to the anterior base of the phallus

Table 3

Childhood assessment (at age 4 years and 8 years)

ParametersUnits/optionsParametersUnits/options
GeneralSurgery
 Date of Assessmentdd/mm/yyyy Left Gonad BiopsyYes/ No/ Not known
 Age at Assessmentyears Right Gonad BiopsyYes/ No/ Not known
 Weightkg Left GonadectomyYes/ No/ Not known
 Heightcm Right GonadectomyYes/ No/ Not known
 BMIkg/m2 Genital reconstructive surgery**None/ clitoral surgery / vaginal surgery / labioscrotal surgery / hypospadias surgery / urethral surgery other than hypospadias; age
 Mothers Heightcm Reasons for genital reconstructive surgeryFunctional / cosmesis / both
 Fathers Heightcm Post Surgical ComplicationsYes/ No/ Not known; if yes, describe.
 Mid parental heightcm
 Original Sex AssignedMale/ Female/ Both/ Not assigned/ OtherPsychosocial, Gender Identity
 Current GenderMale/ Female/ Both/ Not assigned/ Other Any Change in Legal SexYes/ No/ Not known
 Child raised asMale/ Female/ Both / Other Psychosocial Support Offered to ParentsYes/ No/ Not known
 Associated Conditions* Ongoing Psychosocial Support for parentsYes/ No/ Not known
 Known SyndromeYes/ No Psychosocial Support Offered to ChildYes/ No/ Not known
Bone age Ongoing Psychosocial Support for ChildYes/ No/ Not known
 Bone Age datedd/mm/yyyy Age-appropriate Information to ChildYes/ No/ Not known
 Bone age resultyears Has Child Questioned Their GenderYes/ No/ Not known
 Bone age methodTW20/ Radius-ulna-short bone/ Greulich & Pyle Is Child Distressed About Gender Identity or AssignmentYes/ No/ Not known
External PhenotypeMedication
 MeatusTypical female/ Perineal/ Scrotal/ Penoscrotal/ Penile/ Coronal/ Typical male TestosteroneYes (IM, Oral, Transdermal)/ No/ Not known
 Left Gonad LocationImpalpable/ Inguinal/ Inguinoscrotal/ Labioscrotal OestrogenYes (IM, Oral, Transdermal)/ No/ Not known
 Right Gonad LocationImpalpable/ Inguinal/ Inguinoscrotal/ Labioscrotal DHTYes (IM, Oral, Transdermal)/ No/ Not known
 Genital Tubercle Length, <10/ 10-20/ 21-25/ 26-30/ >30 mm Aromatase InhibitorYes/ No/ Not known
 Phallus SizeWithin/ Below/ Above the reference range for male; Within/ Below/ Above the reference range for female GnRH analoguesYes/ No/ Not known
 Labioscrotal FusionYes/ No GlucocorticoidsYes/ No/ Not known
 External Masculinisation Score (EMS) FludrocortisoneYes/ No/ Not known
 External Genitalia Score (EGS) Other drugsYes/ No/ Not known
Internal PhenotypeLab Tests
 Imaging Modality- Left GonadUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy LHLow/ Normal/ High/ Not known
 Imaging Modality- Right GonadUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy FSHLow/ Normal/ High/ Not known
 Left Gonad MorphologyAbsent/ Streak/ Testis/ Ovary/ Ovotestis/ Other AMHLow/ Normal/ High/ Not known
 Right Gonad MorphologyAbsent/ Streak/ Testis/ Ovary/ Ovotestis/ Other Inhibin BLow/ Normal/ High/ Not known
 Imaging Modality- UterusUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy AndrostenedioneLow/ Normal/ High/ Not known
 Uterus MorphologyAbsent/ Müllerian remnants/ rudimentary/ Normal/ Not known Total TestosteroneLow/ Normal/ High/ Not known
 Imaging Modality- Left Fallopian TubeUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy Free TestosteroneLow/ Normal/ High/ Not known
 Imaging Modality- Right Fallopian TubeUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy DihydrotestosteroneLow/ Normal/ High/ Not known
 Left Fallopian Tube MorphologyAbsent/ Rudimentary/ Normal/ Not known OestradiolLow/ Normal/ High/ Not known
 Right Fallopian Tube MorphologyAbsent/ Rudimentary/ Normal/ Not known 17-OHPLow/ Normal/ High/ Not known
 Distance- Vaginal Confluence to Bladder Neckcm Urine steroidsNormal/ Abnormal
 Distance- Vaginal Confluence to Introituscm hCG Stimulation TestSpecify protocol
 Imaging Modality- Left Vas DeferensUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy Adrenal Stimulation TestSpecify protocol
 Imaging Modality- Right Vas DeferensUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy 11-deoxycortisolLow/ Normal/ High/ Not known
 Left Vas Deferens MorphologyAbsent/ Rudimentary/ Normal/ Not known PregnenoloneLow/ Normal/ High/ Not known
 Right Vas Deferens MorphologyAbsent/ Rudimentary/ Normal/ Not known 17-OH PregnenoloneLow/ Normal/ High/ Not known
 DHEALow/ Normal/ High/ Not known

*Associated conditions: CNS, Heart, Renal, Skeletal, Skin, ENT, Eyes, Blood and Lymp, Craniofacial, Adrenal, GI Tract, Haematological, Respiratory, SGA (Small for Gestational Age), Short stature, Non-defined syndrome, Other. ** Genital reconstructive surgery field may be repeated.

Table 4

Adolescent assessment (at start of puberty and end of puberty)

ParametersUnits/ optionsParametersUnits/ options
GeneralSurgery
 Date of Assessmentdd/mm/yyyy Left Gonad BiopsyYes/ No/ Not known
 Age at Assessmentyears Right Gonad BiopsyYes/ No/ Not known
 Weightkg Left GonadectomyYes/ No/ Not known
 Heightcm Right GonadectomyYes/ No/ Not known
 BMIkg/m2 Genital reconstructive surgery**None/ clitoral surgery / vaginal surgery / labioscrotal surgery / hypospadias surgery / urethral surgery other than hypospadias/ phalloplasty; age
 Mothers Heightcm Vaginal HypoplasiaYes / No/ Not known
 Fathers Heightcm Medical management of vaginal hypoplasiaDilation / Surgery / None
 Mid parental heightcm Type of VaginoplastyIntestinal / Peritoneal / Davydov / Vecchietti / Baloon / Other
 Original Sex AssignedMale/ Female/ Both/ Not assigned/ Other Post Surgical ComplicationsYes/ No/ Not known; if yes, describe.
 Current GenderMale/ Female/ Both/ Not assigned/ Other Gonadal Germ Cell CancerYes/ No/ Not known
 Adolescent raised asMale/ Female/ Both / Other Left GonadNone/ GCNIS/ Gonadoblastoma/ Seminoma/ Non-seminoma/ Dysgerminoma/ Other
 Associated Conditions* Right GonadNone/ GCNIS/ Gonadoblastoma/ Seminoma/ Non-seminoma/ Dysgerminoma/ Other
 Known SyndromeYes/ NoPsychosocial, Gender Identity
Bone age, bone mineral density Change in Legal SexYes/ No/ Not known
 Bone Age datedd/mm/yyyy Psychosocial Support Offered for ParentsYes/ No/ Not known
 Bone age resultyears Ongoing Psychosocial Support for parentsYes/ No/ Not known
 Bone age methodTW20/ Radius-ulna-short bone/ Greulich & Pyle Psychosocial Support Offered to ChildYes/ No/ Not known
 Bone mineral densityYes/ No/ Not known Ongoing Psychosocial Support for ChildYes/ No/ Not known
 Bone Mineral Density Datedd/mm/yyyy Age-appropriate Information to ChildYes/ No/ Not known
 Bone Mineral Density ResultOsteopenia/ Osteoporosis/ Normal Has Child Questioned Their GenderYes/ No/ Not known
Puberty Is Child Distressed About Gender Identity or AssignmentYes/ No/ Not known
 Breast stage1/ 2/ 3/ 4/ 5/ Not Known Physical or Mental Health Status Interferes with Daily Life Activities (education, work)Yes / Partially / No
 Genital stage1/ 2/ 3/ 4/ 5/ Not Known Physical or Mental Health Status Interferes with Social Activities (hobbies, friends, relations)Yes / Partially / No
 Axillary hair stage1/ 2/ 3/ 4/ 5/ Not KnownMedication
 Pubic hair stage 1/ 2/ 3/ 4/ 5/ Not Known TestosteroneYes (IM, Oral, Transdermal)/ No/ Not known
 Left testicular volumeml OestrogenYes (IM, Oral, Transdermal)/ No/ Not known
 Right testicular volumeml DHTYes (IM, Oral, Transdermal)/ No/ Not known
 Stretched penile lengthcm Aromatase InhibitorYes/ No/ Not known
 Spontaneous pubertyYes/ No/ Not known GnRH analoguesYes/ No/ Not known
 Pubertal inductionYes/ No/ Not known GlucocorticoidsYes/ No/ Not known
 Induction with oestrogenYes (Oral, Transdermal)/ No/ Not known FludrocortisoneYes/ No/ Not known
 Induction with testosteroneYes (Oral, Transdermal)/ No/ Not known Other drugsYes/ No/ Not known
 MenarcheSpontaneous/ Induced/ Not knownLab Tests
 HirsutismYes/ No/ Not known LHLow/ Normal/ High/ Not known
 GynaecomastiaYes/ No/ Not known FSHLow/ Normal/ High/ Not known
Internal Phenotype AMHLow/ Normal/ High/ Not known
 Imaging Modality- Left testisUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy Inhibin BLow/ Normal/ High/ Not known
 Imaging Modality- Right testisUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy AndrostenedioneLow/ Normal/ High/ Not known
 Left testis MorphologyAbsent/ Normal/ Small/ Abnormal Total TestosteroneLow/ Normal/ High/ Not known
 Right testis MorphologyAbsent/ Normal/ Small/ Abnormal Free TestosteroneLow/ Normal/ High/ Not known
 Imaging Modality- UterusUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy DihydrotestosteroneLow/ Normal/ High/ Not known
 Uterus MorphologyAbsent/ Normal/ Hypoplastic/ Abnormal OestradiolLow/ Normal/ High/ Not known
 Imaging Modality- Left ovaryUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy 17-OHPLow/ Normal/ High/ Not known
 Imaging Modality- Right ovaryUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy Urine steroidsNormal/ Abnormal
 Left ovary MorphologyAbsent/ Streak/ Normal/ Polycystic hCG Stimulation TestSpecify protocol
 Right ovary MorphologyAbsent/ Streak/ Normal/ Polycystic Adrenal Stimulation TestSpecify protocol
Sexual Health 11-deoxycortisolLow/ Normal/ High/ Not known
 MensesYes/ Primary amenorrhoea/ Secondary amenorrhoea PregnenoloneLow/ Normal/ High/ Not known
 Age at Menopause 17-OH PregnenoloneLow/ Normal/ High/ Not known
 Fertility DesiredYes/ No/ Not known DHEALow/ Normal/ High/ Not known
 Tissue StorageYes/ No/ Not known
 Sperm AssessmentYes/ No/ Not known
 Sperm count, per million/mlx million per ml/ Normal/ Abnormal/ Not Reported
 Number of Offspring
 Assisted ConceptionYes/ No/ Not known

*Associated conditions: CNS, Heart, Renal, Skeletal, Skin, ENT, Eyes, Blood and Lymp, Craniofacial, Adrenal, GI Tract, Haematological, Respiratory, SGA (Small for Gestational Age), Short stature, Non-defined syndrome, Other. ** Genital reconstructive surgery field may be repeated.

Much less evidence is available to guide timing of clinical revision in adulthood (Table 5). In favour of standardised assessment of young individuals aged 18–25 years is that they are in the process of gaining independence and have recently transitioned to adult care. Many young people are newly forming intimate relationships, which potentiates new concerns and/or required healthcare intervention. Topics such as sexual function, sexual orientation, and gender identity may become central in their lives. In addition, baseline information on typical health issues in adulthood such as bone mineral density, blood pressure, and obesity should be collected. Issues around fertility and forming a family may dominate between ages 25 and 40 years.

Table 5

Adult assessment (once per interval: 18-25; 25-40; 40-60; 60-75 years)

ParametersUnits/ optionsParametersUnits/ options
GeneralSurgery
 Date of Assessmentdd/mm/yyyy Left Gonad BiopsyYes/ No/ Not known
 Age at Assessmentyears Right Gonad BiopsyYes/ No/ Not known
 Weightkg Left GonadectomyYes/ No/ Not known
 Heightcm Right GonadectomyYes/ No/ Not known
 BMIkg/m2 Genital reconstructive surgery**None/ clitoral surgery / vaginal surgery / labioscrotal surgery / hypospadias surgery / urethral surgery other than hypospadias/ phalloplasty; age
 Mothers Heightcm Vaginal HypoplasiaYes / No/ Not known
 Fathers Heightcm Medical management of vaginal hypoplasiaDilation / Surgery / None
 Mid parental heightcm Type of VaginoplastyIntestinal / Peritoneal / Davydov / Vecchietti / Baloon / Other
 Original Sex AssignedMale/ Female/ Both/ Not assigned/ Other Post Surgical Complications of genital surgeryYes/ No/ Not known; if yes, describe.
 Current GenderMale/ Female/ Both/ Not assigned/ Other Gonadal Germ Cell CancerYes/ No/ Not known
 Adult raised asMale/ Female/ Both / Other Left GonadNone/ GCNIS/ Gonadoblastoma/ Seminoma/ Non-seminoma/ Dysgerminoma/ Other
 Associated Conditions* Right GonadNone/ GCNIS/ Gonadoblastoma/ Seminoma/ Non-seminoma/ Dysgerminoma/ Other
 Known SyndromeYes/ No Breast surgeryNone / breast reconstruction/augmentation/ reduction/ mastectomy
Bone age, bone mineral density Post Surgical Complications of Breast SurgeryYes/ No/ Not known; if yes, describe
 Bone age datedd/mm/yyyyPsychosocial, Gender Identity
 Bone age resultyears Change in Legal SexYes/ No/ Not known
 Bone age methodTW20/ Radius-ulna-short bone/ Greulich & Pyle Psychosocial Support Yes/ No/ Not known
 Bone mineral densityYes/ No/ Not known Ongoing Psychosocial SupportYes/ No/ Not known
 Bone Mineral Density Datedd/mm/yyyy Full information about conditionYes/ No/ Not known
 Bone Mineral Density ResultOsteopenia/ Osteoporosis/ Normal Gender roleFemale/ Male/ Both/ Neither/ Not known
Puberty Physical or Mental Health Status Interferes with Daily Life Activities (education, work)Yes / Partially / No
 Breast stage1/ 2/ 3/ 4/ 5/ Not Known Physical or Mental Health Status Interferes with Social Activities (hobbies, friends, relations)Yes / Partially / No
 Genital stage1/ 2/ 3/ 4/ 5/ Not KnownSexual Health
 Axillary hair stageYes/No/ Not Known MensesYes/ Primary amenorrhoea/ Secondary amenorrhoea
 Pubic hair stage 1/ 2/ 3/ 4/ 5/ 6/Not Known Age at Menopauseyears
 Left testicular volumeml Fertility DesiredYes/ No/ Not known
 Right testicular volumeml Tissue StorageYes/ No/ Not known
 Spontaneous pubertyYes/ No/ Not known Sperm AssessmentYes/ No/ Not known
 Pubertal inductionYes/ No/ Not known Sperm count, per million/mlx million per ml/ Normal/ Abnormal/ Not Reported
 Induction with oestrogenYes (Oral, Transdermal)/ No/ Not known Number of Offspring
 Induction with testosteroneYes (IM, Oral, Transdermal)/ No/ Not known Assisted ConceptionYes/ No/ Not known
 MenarcheSpontaneous/ Induced/ Not knownMedication
 HirsutismYes/ No/ Not known TestosteroneYes (IM, Oral, Transdermal)/ No/ Not known
 GynaecomastiaYes/ No/ Not known Oestrogen (E)Yes (IM, Oral, Transdermal)/ No/ Not known
Co-morbidities DHTYes (IM, Oral, Transdermal)/ No/ Not known
 OsteoporosisYes/ No/ Not known Aromatase InhibitorYes/ No/ Not known
 Type II DiabetesYes/ No/ Not known GnRH analoguesYes/ No/ Not known
 Chronic Kidney DiseaseYes/ No/ Not known GlucocorticoidsYes/ No/ Not known
 Chronic Liver DiseaseYes/ No/ Not known FludrocortisoneYes/ No/ Not known
 Central Nervous SystemYes/ No/ Not known Progestin (P)Yes (Oral, Subcutaneous, IM, IUD) / No/ Unknown
 HypertensionYes/ No/ Not known Combined E/P (HRT/OC***)Yes (Oral, Transdermal, Vaginal)/ No/ Not known
 OtherYes/ No/ Not known; if yes, describe Other drugsYes/ No/ Not known
Internal PhenotypeLab Tests
 Imaging Modality- Left testisUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy LHLow/ Normal/ High/ Not known
 Imaging Modality- Right testisUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy FSHLow/ Normal/ High/ Not known
 Left testis MorphologyAbsent/ Normal/ Small/ Abnormal AMHLow/ Normal/ High/ Not known
 Right testis MorphologyAbsent/ Normal/ Small/ Abnormal Inhibin BLow/ Normal/ High/ Not known
 Imaging Modality- UterusUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy AndrostenedioneLow/ Normal/ High/ Not known
 Uterus MorphologyAbsent/ Normal/ Hypoplastic/ Abnormal Total TestosteroneLow/ Normal/ High/ Not known
 Imaging Modality- Left ovaryUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy Free TestosteroneLow/ Normal/ High/ Not known
 Imaging Modality- Right ovaryUS/ MRI/ Genitogram/ Laparoscopy/ Genitoscopy DihydrotestosteroneLow/ Normal/ High/ Not known
 Left ovary MorphologyAbsent/ Streak/ Normal/ Polycystic OestradiolLow/ Normal/ High/ Not known
 Right ovary MorphologyAbsent/ Streak/ Normal/ Polycystic 17-OHPLow/ Normal/ High/ Not known
 Urine steroidsNormal/ Abnormal
 hCG Stimulation TestSpecify protocol
 Adrenal Stimulation TestSpecify protocol
 11-deoxycortisolLow/ Normal/ High/ Not known
 PregnenoloneLow/ Normal/ High/ Not known
 17-OH PregnenoloneLow/ Normal/ High/ Not known
 DHEALow/ Normal/ High/ Not known

*Associated conditions: CNS, Heart, Renal, Skeletal, Skin, ENT, Eyes, Blood and Lymp, Craniofacial, Adrenal, GI Tract, Haematological, Respiratory, SGA (Small for Gestational Age), Short stature, Non-defined syndrome, Other; ** Genital reconstructive surgery field may be repeated; ***Hormonal replacement treatment/Oral contraceptives

During the age intervals of 40–60 and 60–80 years, long-term effects of treatment or (lack of) hormonal treatment and comorbidities may become apparent (8). Physical and mental health issues of adults living with a DSD are major determinants of overall quality of life (QoL) (4). It is therefore crucial to capture such information in order to allow for future research and appropriate management.

Genetic and biochemical data

Most causes of DSD are genetic; however, drugs, environmental toxins, and maternal and placental causes are also relevant and/or may influence outcomes. A clear diagnosis can determine the spectrum of potentially affected organs, current/future health consequences, and treatment options (8).

A comprehensive diagnostic approach consists of an extensive family history over at least three generations, as well as a physical exam of the whole body which includes the genital organs. This will then guide the clinician towards further diagnostic imaging, biochemical and genetic studies. Guidelines for the clinical, biochemical, and genetic work-up of DSD have been published elsewhere (12, 15, 16).

Collecting genetic information, together with clinical and biochemical data, in a centralised registry allows identification and characterisation of DSD subgroups, including those for which a genetic diagnosis has not been achieved so far. It is possible then to test the diagnostic reliability of specific biochemical and genetic parameters and their usefulness for implementation in clinical diagnostic guidelines. It will also enable studies on the impact of a molecular genetic diagnosis on outcome. Indeed, almost 50% of individuals who have a 46,XY DSD have no genetic diagnosis, and it remains debatable whether and how this impacts management and overall QoL (17).

Although DSDs are congenital conditions, the function of affected organs may decline over time, e.g. testicular function in 45,X/46,XY boys (18). Therefore, any initially performed diagnostic laboratory investigation may need to be repeated, if in doubt and of therapeutic consequence. Hormonal and other drug treatments need to be controlled with regular intervals for correct dosing, effectiveness and side effects. Biochemical parameters that qualify best for treatment monitoring need to be identified based on prospectively collected data.

In some individuals who have an unknown cause of their condition, genetic work-up has been performed years ago with methods that are currently outdated. In others, whole exome or whole genome sequencing may reveal variants of unknown significance or monogenetic variants in established DSD genes that do not clearly explain the observed phenotype (e.g. heterozygous MAMLD1 mutations) (19). Finally, DSD genetics may be more complex than initially thought, as demonstrated recently (20). Therefore, genetic results may also require re-evaluation as new knowledge is gained over time.

Medical fields

Family data

A detailed family history, including fertility, is essential to explore possible inheritance mechanisms and to lend support for molecular genetic investigations in individuals with milder phenotypes. Phenotypic variability within families may be broad and may comprise subfertility/infertility as the only sign, depending on the severity of the mutation (21, 22).

Associated conditions

Several comorbidities and non-gonadal organ dysfunctions are associated with specific DSDs (23). Further exploration of these associations is important for targeted follow-up of affected individuals and for understanding the mechanisms of disease. As many DSD conditions are caused by mutations in transcription factors that regulate the development of several organ systems, this may result in combined functional defects, as for example in WT1 (kidney involvement), NR5A1 (adrenal involvement, spleen hypoplasia) or GATA4 (cardiac defects) mutations (24, 25, 26, 27). Associated conditions are mostly found in chromosomal DSD such as 45,X/46,XY and may only develop over time, requiring medical attention at each follow-up visit, for example cardiac surveillance in all individuals who have 45,X/46,XY mosaicism (18, 28).

External and internal genital phenotype

As genital photography and storage faces ethical and legal challenges, standardised tools are needed to objectively describe the genital aspect in detail. Qualitative visual scales such as the Prader (29) or Quigley (30) scales are highly observer dependent and do not consider internal and external genital status separately. The anogenital distance correlates with prenatal androgen exposure but lacks standardisation and is difficult to perform in children above 1 year (31). The External Masculinization Score (EMS) is a practical and objective tool, has good inter-observer reliability and correlates with relevant clinical outcomes (12, 32, 33). Limitations include its restricted applicability – only male neonates – and dichotomous nature (e.g. micropenis yes/no). To overcome these problems, a modified EMS, termed “external genitalia score” (EGS), has been developed. The EGS assesses the same anatomical landmarks as EMS while using a gender-neutral vocabulary applicable in all infants up to 2 years of age, and a more gradual scale, reflecting the naturally occurring phenotypic variability of external genitalia. Reference ranges for a mixed European population have been determined (S van der Straaten, A Springer, A Zecic, D Hebenstreit, U Tonnhofer, A Gawlik, M Baumert, K Szeliga, S Debulpaep, A Desloovere et al. The external genitalia score (EGS): A European multicenter validation study 2019; personal communication). Additional parameters such as penile curvature and tissue quality are likely related to (surgical) outcome, but these are currently ill-defined and require further study. Reliable assessment of internal genitalia requires imaging and sometimes surgical procedures such as laparoscopy. Knowledge on the internal anatomy can be helpful in cases where the initial sex/gender of rearing is unclear and to foresee possible complications. Imaging techniques have significant differences in sensitivity, sensibility, and invasiveness. In the longer term, meta-analysis of data will provide further insights on the procedure of choice in specific situations.

The genital phenotype and other sex characteristics change as the individual grows or as a result of hormonal treatment or surgery. Frequent genital inspection is not recommended, but may be helpful in specific situations, especially as it can help parents and children / adolescents to understand that there is a natural variation in clitoral sizes and genital aspect or to discuss eventual parental or patient worries. For example, in 46,XX individuals who have CAH, clitoral size may decrease in response to glucocorticoid treatment after the newborn period. This finding is often very reassuring for parents and may actually convince them that the genital aspect has indeed become unremarkable for a lay person taking care of their baby. On the other hand, clitoral size may increase in periods of undertreatment or non-compliance (34, 35) and/or adolescent girls may feel insecure about its aspect. Thoughtful genital inspection in an adolescent girl, after having obtained her consent, may sometimes help her discussing eventual worries about the genital aspect and/or reassure her that clitoral sensitivity is most important and that the clitoral aspect falls within the natural variation. Gonadal failure may result in the lack or arrest of pubertal development. In such cases, it is important to document genital pubertal progression at the suggested time intervals. Suspicion of complications, e.g. fistulae after hypospadias surgery will also require a genital exam.

In adult life, psychosexual function is an even more important outcome parameter and should be discussed as suggested in Table 5; sometimes, depending on the specific question (eg worries about penile length), this will need to be done in parallel with a genital examination (1 S van der Straaten, A Springer, A Zecic, D Hebenstreit, U Tonnhofer, A Gawlik, M Baumert, K Szeliga, S Debulpaep, A Desloovere et al. The external genitalia score (EGS): A European multicenter validation study 2019; personal communication).

Anthropometric data, body composition and bone health

Documentation of birth weight and length, growth, body composition and bone health parameters is crucial as it may reveal the long-term outcomes of childhood processes such as the postnatal hypothalamic-pituitary-gonadal activation (the ‘mini-puberty’) and growth patterns in DSD other than Turner syndrome (TS) and Klinefelter syndrome (KS), where evidence is currently scarce. For example, no data are available on the prevalence and extent of catch-up growth in children with atypical genitalia who were born small for gestational age. In individuals with 45X/46XY karyotypes, growth hormone treatment has variable effects and may need to be optimised (36, 37). Age at start of puberty induction and dosing of sex steroids may affect the growth pattern and body proportions (38). Glucocorticoid overtreatment compromises growth and leads to increased weight and BMI in the longer term (39). Both androgens and oestrogens are important for bone mass accrual and maintenance. Overtreatment with glucocorticoids, vitamin D deficiency, physical activity, and hereditary factors may influence bone health (40).

Medical treatments

Some treatments are offered early in life, but evidence of their long-term efficacy may be lacking, for example, testosterone or dihydrotestosterone (DHT) for micropenis (41). The use of some medications is experimental (e.g. aromatase inhibitors to block the effect of sex hormones (42, 43) or metformin to avoid metabolic consequences (44)), but others, such as growth hormone, gluco- and mineralocorticoids, l-thyroxin, insulin and sex hormone replacement therapy are frequently used in DSD and need constant surveillance and adjustments (45, 46, 47). Standardised guidelines are lacking for most DSD conditions, with the exception of TS and KS (45, 48).

Lifelong steroid and sex hormone replacement therapy may induce side effects that negatively (or positively) impact QoL (4) and optimal dosing may vary with age (49, 50). Very few studies address medical needs to optimise sexual function and to avoid secondary health consequences, especially at older ages. In addition, treatment regimens differ widely across centres and comparison of these protocols may further improve patient management and health-related QoL in the future (2, 51). Large-scale registration and in-depth analysis of comorbidities and of chronic use of certain medications aim to improve care and to positively alter outcomes.

Particular attention has been given to the prenatal treatment of a foetus possibly affected by 21-hydroxylase deficiency with dexamethasone administered to the mother. Benefit-risk ratio is still unclear, and it is currently regarded as experimental (35). From another perspective, drugs such as pain killers given to pregnant women and (environmental) toxins may affect foetal sexual development and fertility (52). This important domain is largely unexplored, and collecting detailed information related to this topic is essential for future exploration.

Fertility and documentation of gonadal cancers

Fertility is strongly reduced in all forms of DSD, for biological and/or psychosocial reasons. Contemporary assisted reproductive techniques (ART) can increase chances to have biological children for some azoospermic individuals with 46,XY DSD and for some who have viable eggs (53, 54). Uterus transplantations have resulted in live births (55). It is anticipated that improvement of hormonal therapies and new technologies (e.g. in vitro generation of induced primordial germ cell-like cells) (56) may further increase fertility rates in the future. Assessment and documentation of reproductive capacity of the gonads independent of the patients’ social gender has the aim of understanding condition-specific fertility chances (57). It can also facilitate access to international research protocols in this field through recruitment of registered patients.

The mechanisms underlying germ cell cancer development in DSD are increasingly understood. Routine prophylactic gonadectomy to prevent germ cell cancer development is no longer recommended in all individuals at risk; guidelines for selective gonadectomy and surveillance of retained gonads have been published (58, 59). Given the recent practice changes, no long-term outcome data on tumour risk in adulthood are available today, and with the possible exception of complete androgen insensitivity (59, 60), individualised management is hampered by a paucity of condition-specific data (58, 61). Therefore, current recommendations may need to be adjusted based on future insights. With a molecular genetic diagnosis more often reached today, and with systematic registration of pathology results and centralised review of challenging cases, further progress in this matter can be achieved (62).

Surgical fields

Childhood surgery

There are few evidence-based indications for gonadal or genital surgery in early childhood. Gonadal biopsy may, in exceptional cases, support important decisions, for example in relation to sex of rearing in the context of suspected (ovo)testicular DSD (63). Following international criticism of early genital surgery, many centres have restricted such procedures (9). Although debated, early surgery is still offered by some centres for 46,XX CAH patients with severe genital virilisation and for 46,XY patients with hypospadias. Other centres have restricted such procedures and consider alternative options such as raising severely virilised 46,XX CAH children as males and offer extensive parental support to enhance the information and decision-making process. The developmental, familial, and societal impact of growing up with atypical-looking genitalia is currently not well understood. Psychosocial support appears crucial, and detailed documentation of such decisions in a multicentre registry is essential to allow urgent studies on their appropriateness and long-term consequences (64). Systematic registration can also demonstrate the time and pace needed to definitively implement the proposed practice changes.

There is no scientific evidence nor expert consensus on how surgery or refraining from surgery impacts the individual, family, society, or risk of stigmatisation (1). Standardised and detailed documentation of performed procedures, complications and reasons for and outcome of (non-) intervention are therefore crucial (9). As the focus of many performed genital surgeries nowadays is more on function than in relation to gender assignment, a specific description should be used for the intervention or the reasons to intervene rather than referring to ‘feminising / masculinising’ genital surgery.

Genital examinations

Genital examinations should be limited and should have a clear and transparent purpose. Living with atypical-looking genitals and/or having had genital surgery may pose psychological and psychosexual challenges that require timely referral to a psychologist or sexologist. This person can then further perform a psychological evaluation, using standardised diagnostic measures and propose appropriate support if needed. The applied methodology depends on the specific goal of such an assessment. No DSD-specific questionnaires to assess psychological and/or psychosexual functioning currently exist, and interpretation of results is seriously hampered by methodological limitations, highlighting the need for psychologists with good knowledge of and experience with the various conditions and for further professional training in this field (65).

Follow-up of adults

Follow-up of adults who had genital surgery in infancy is rarely organised in the routine clinical setting. High-quality outcome and longitudinal studies are scarce. Difficulties include differences in technical terms, modifications of surgical techniques over the years, heterogeneity of DSD conditions and reporting bias of surgeons towards the techniques they are most experienced with (66). Comprehensive assessment ideally includes recording complications and redo surgery (also in adulthood), cosmetic appearance, functional outcome (micturition, sexuality), and quality of psychosexual life as a minimum, all in relation to preoperative findings and assessed both by a professional and by self-assessment (67, 68, 69, 70).

The hypospadias objective penile evaluation score (HOPE) has been designed for standardised cosmetic evaluation by a professional of hypospadias surgery (71). Although practical and objective, HOPE has important shortcomings, such as the use of genital pictures, lack of evaluation of the scrotum and of possibilities for self-assessment, most notably of penile size, which is considered crucial by many patients (72). A subjective cosmetic evaluation of hypospadias surgery can be obtained with the penile perception score (PPS) and its paediatric variant (PPPS) (73, 74). All the above lack functional parameters such as micturition pattern and erection and ejaculation capacity. A suggestion for a non-photography-based modified HOPE score, with addition of relevant functional and self-perceived assessments is provided in Supplementary Table 1 (see section on supplementary data given at the end of this article).

Different measures have been used for gynaecological and sexual function assessments of the female genitalia (e.g. (66, 70, 75)). Standardised tools for assessing long-term functional and cosmetic outcome of female genital surgery are in development. Items that are important to assess are listed in Supplementary Table 2.

Psychosocial fields

Trends in sex assignment have changed over the years (33). Sex and gender are fundamental in the development of a person’s identity, as well as the individual’s integrity, self-esteem, and social relations. Inappropriate focus or a normative perspective on genital, sexual, and psychological issues may cause annoyance or stigmatisation. Therefore, questions about a person’s gender experience and gender well-being should be posed with respect for the individual’s integrity and in an open-ended way that does not presume a particular gender or increase shame and stigma (65). Both children and adolescents should be given the possibility to talk about these issues without a parent being present (13).

Assessment of an individual’s mental well-being and need for psychosocial support should be part of standard care throughout life. Physical or mental health problems are highly prevalent in individuals who have a DSD (2, 8). Importantly, not the specific diagnosis but the personal health status predicts QoL (4). Overall, individuals with a DSD report good QoL but studies are often contradictory, possibly due to differences in local treatment and care, age and cultural context and differences in methodology. Appropriate QoL questionnaires should focus on social and psychological domains that are relevant for individuals who have a DSD (76). In addition, patient-reported outcome measures related to QoL at all life stages are considered most crucial by patients, and it is clear that they have a central place in holistic care (77). Formal QoL assessment in the context of routine clinical practice is unusual, but as a minimum, it is suggested to record the impact of the condition on the patients’ daily life by including a relevant proxy for this. While awaiting more specific key questions, preferably developed by support groups and other stakeholders, a generic set of simple questions is proposed here, which can be adjusted to all ages.

Considering all conditions together, the prevalence of gender dysphoria is only slightly increased in DSD. However, assessing gender identity and gender-related behaviour according to a strict binary or pathologising model will insufficiently capture the broad spectrum of gender-related outcomes (78). Currently, hardly any instrument is available that allows gender assessment according to a spectral rather than a bimodal paradigm. Therefore, new measures and instruments, using a non-binary vocabulary and taking all possible gender outcomes into account need to be developed. In addition, gender role behaviour rather than gender well-being has been given (too) much attention in the past. Indeed, it is crucial not to misinterpret behaviour or sexual orientation as signs of gender dysphoria (11).

From the beginning, psychosocial support for parents, aiming at an enhanced understanding of the medical context and the diagnostic investigations are crucial factors for coping with psychological distress (79). Parent-child bonding, coping abilities and symptoms of stress are important indicators of parental needs on this matter (12). In the presence of a genital difference, parents need guidance on how to raise resilient children and how to communicate early with their child about the condition, including consequences for gender development and past and future treatment options (80). To what extent psychosocial support and early information may contribute to optimisation of outcomes has never been documented in the context of DSD. Providing further evidence in favour of such support may convince policy makers to invest in psychological counselling, as an important part of preventive care and as a valuable alternative to genital surgery, amongst others (81, 82).

Many registries such as I-DSD are developing sections that include possibilities for self-reporting of relevant outcome measures, such as reasons for genital surgery or not having such surgery, and self-reported QoL. Altogether, considering the voices of people with DSD and their parents, research and care of DSD can move from a researcher-driven to a participant-driven approach.

Conclusions and perspectives

Consensus was reached on standardised assessments of individuals who have a DSD and on the ages at which clinical revision should be performed in order to capture crucial developmental milestones and/or long-term consequences of the various conditions. In the clinical setting, the tool will ensure and support a high quality of clinical care. Long-term and wide use of this instrument, for example, through the I-DSD Registry, will allow answering critical research questions in the future specifically in relation to outcome, treatment options, comorbidities in adult age and fertility. In addition, patient-reported outcome measures, obtained through patient portals, are expected to become increasingly important and may also be implemented in the I-DSD Registry in the near future.

Supplementary data

This is linked to the online version of the paper at https://doi.org/10.1530/EJE-19-0363.

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 article is based upon work from COST Action DSDnet, supported by COST (European Cooperation in Science and Technology) as BM1303. MC holds a senior clinical investigator grant from the Research Foundation Flanders. CEF is supported by the Swiss National Science Foundation (grant number 320030-146127). AN holds a senior clinical research position funded by Karolinska and Stockholm County Council. BK is supported by a grant from the European Union Seventh Framework Programme (FP7/2007-2013) grant n° 305373.

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    Schema of the longitudinal I-DSD registration tool showing time points, ages for data entry, starting at the age of diagnosis. Neonatal data, including genetic information if available, should always be entered regardless of the age at diagnosis.