Paediatric Urology

20. DISORDERS/DIFFERENCES OF SEX DEVELOPMENT

20.1. Introduction

Formerly referred to as ‘intersex disorders’, this constellation of conditions has been the subject of a consensus document in which it was decided that the term ‘intersex’ should be changed to ‘disorders/differences of sex development’ (DSD), however, the original term is still used in the resolution of the Parliamentary Assembly of the Council of Europe (see later in this section) [1188].

The new classification has arisen due to advances in knowledge of the molecular genetic causes of abnormal sexual development, controversies inherent to clinical management, and ethical issues. Controversial and negative terminology, e.g. ‘pseudohermaphroditism’ and ‘hermaphroditism,’ have been renamed according to new pathophysiological insights. Moreover, some conditions presenting with severe male genital malformation that could not previously be categorised, such as penile agenesis and cloacal exstrophy, have now also been included. The term ‘disorders/differences of sex development’ is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal or anatomical sex.

In addition, in 2017, the Parliamentary Assembly of the Council of Europe decided on a resolution termed ‘Promoting the human rights of and eliminating discrimination against intersex people’ [1189]. The Assembly concluded that the majority of ‘intersex’ people (cited verbatim from the resolution) were physically healthy and that only a few suffered from medical conditions that put their health at risk. Furthermore, they stated that the prevailing medical view at that time was that the bodies of ‘intersex’ children could, and should, be made to conform to either a male or a female paradigm - often through surgical and/or hormonal intervention - and that this should be performed as early as possible so that these children could then be raised in the gender corresponding to their assigned sex. The Parliamentary Assembly considered that this approach involved serious breaches of physical integrity and autonomy, with many cases concerning very young children or infants who were unable to give informed consent and whose gender identity was unknown.

Therefore, the Parliamentary Assembly called on Council of Europe member states to effectively protect children’s rights to physical integrity and bodily autonomy, and to empower ‘intersex’ people with the following rights: medically unnecessary ‘sex-normalising’ surgery, sterilisation and other treatments practised on ‘intersex’ children without their informed consent should be prohibited, and additionally that it must be ensured that, except in cases in which the life of the child is at immediate risk, any treatment that seeks to alter the sex characteristics of the child, including their gonads, genitals or internal sex organs, must be deferred until such time as the child is able to participate in the decision based on the right to self-determination and on the principle of free and informed consent. The Panel refers to the above-mentioned consensus documents, as well as on the Parliamentary Assembly resolution. This chapter will focus on what is relevant for the practising paediatric urologist, as they are likely to be involved in neonates with DSD conditions.

Overall, evidence-based literature on DSD is sparse. There are no RCTs, and most studies are based on retrospective, clinical descriptive studies, or on expert opinion. An exception is made in relation to the risk of gonadal cancer, for which the level of evidence is higher [1190].

Disorders/differences of sex development can present as a prenatal diagnosis, neonatal diagnosis or late diagnosis. Prenatal diagnosis can be based on karyotype or sonographic findings; A neonatal diagnosis is based on genital ambiguity, and a late diagnosis is usually made as a result of early or delayed puberty. In these Guidelines the focus is on the neonatal presentation, where the paediatric urologist plays a more central role. Several publications have appeared over the past few decades exploring the role of prenatal corticosteroid treatment of patients with congenital adrenal hyperplasia. The Endocrine Society still proclaims their use to be restricted to research settings, and that this treatment remains experimental [1191,1192]. For late diagnoses, we refer to endocrinology and gynaecology guidelines on precocious and delayed puberty, where paediatric urologists play a less-central role [1193,1194].

Dealing with neonates with DSD requires a multidisciplinary approach, which should ideally include geneticists, neonatologists, paediatric and adult endocrinologists, paediatric urologists, gynaecologists, psychologists, ethicists, and social workers. Each team member should ideally be experienced in DSD, and a team should have treated enough patients to ensure experience.

A discrepancy is often perceived between research topics proposed by research scientists and those considered important by DSD patients [1195]. As a result of this discrepancy, collaborative networks such as the ‘dsd-LIFE’ consortium have been established to include research scientists, health professionals, patient families, and support groups (available from: https://www.dsd-life.eu/home/index.html. The focus of the DSD-LIFE study is on what patients and caregivers consider to be a priority, and research is then carried out around that issue. In addition, the newly established European Reference Network (ERN), covering rare endocrine conditions (Endo-ERN), considers patient participation in research and database management to be crucial (available from: https://endo-ern.eu/).

20.2. International consensus statements on DSD management

Four consensus statements have been published in regard to the investigations and management of DSD. In general, these statements have focused on the impact of DSD on older age groups and the importance of long-term, prospective, multidisciplinary, multicentre data collection, with a focus on patient-reported outcomes. The ultimate ambition is to preserve physical and psychological function in these future adults [1196]. The consensus proposal from the European Society of Paediatric Radiology task force focused predominantly on imaging modalities and calls for the optimisation of US in initial and interval assessments of anatomy, with MR imaging and cystovaginography used as adjunctive modalities [1197]. The COST Action BM1303 working group consensus statement from Europe raised the concern of the effects of delayed genital and gonadal surgery on physical, psychological and sexual well-being, as well as the potential malignant risks of retained gonads. Support tools need to be developed to help guide affected families and children with a balance struck between surgery and the protection of human rights [1195]. The Canadian consensus statement broadly concurs with the above but differs slightly from their European counterparts. It suggests that sex assignment need not take place at birth, and there should be a recognition of the harms caused in the past by a paucity of information to parents, and that decisions involving surgery should take place involving a shared decision model. Finally, this consensus suggests that data is insufficient to determine the correct timing of surgery [1198].

20.3. Current classification of DSD conditions

Several updates have been published since the International Consensus Conference on ‘intersex’ and its subsequent publications on the classification of the various conditions of DSD. The most recent of these was published by the Global DSD Update Consortium in 2016 [1199]. As the field of DSD is continuously developing, and knowledge and viewpoints change over time, an effort has been made to consider diversity, inclusion and equality, and therefore representatives from support and advocacy groups continue to be invited, with an aim of focussing on patient care and the best possible QoL.

According to the international consensus in 2005, DSDs have been defined as congenital conditions within which the development of chromosomal, gonadal and/or anatomic sex is atypical. The changes that were made according to terminology are as follows:

46XX DSD
This was formerly termed female pseudohermaphrodite, overvirilisation of an XX female, and masculinisation of an XX female. In this group, the vast majority is due to classic congenital adrenal hyperplasia (CAH) with various degrees of masculinisation. Among all DSD conditions combined, 46XX CAH patients comprise approximately 80% of cases. These conditions are extremely important because they can be potentially life-threatening days after birth due to a salt-loss phenomenon, and immediate medical care is mandatory.

46XY DSD
Previously referred to as ‘male pseudohermaphroditism’, undervirilisation of an XY male, and undermasculinisation of an XY male. This group is often quite heterogenous and includes the partial androgen insensitivity syndrome (PAIS), as well as the complete androgen insensitivity syndrome (CAIS) formerly referred to as ‘testicular feminisation.’

Sex chromosome mosaicism DSD (45X; 45X/46XY; 47XXY)
This cohort consists of multiple variants, the most important of which being the mixed gonadal dysgenesis. Many have a normal male phenotype, and others may have asymmetric genitalia. One scrotal half often contains a gonad that is likely to be a testis, whereas the other side is more in keeping with a labia majora with usually no palpable gonad, which will most likely be a streak gonad.

Ovotesticular DSD
This was previously described as a ‘true hermaphrodite’ due to the presence of ovarian and testicular tissue coexisting in the same individual. There is great variability in phenotype with unilateral or bilateral undescended gonads, which can present as one ovary and one testis, or as one or two ovotestes.

Nonhormonal/nonchromosomal DSD
This cohort was recently introduced and includes newborns with cloacal exstrophy, where bladder and intestines are exposed through a midline mesenchymal defect resulting from the failure of the cloacal membrane to retract, and which then ruptures. Others in this cohort include patients with aphallia and severe micropenis. The latter is a normally formed penis with a stretched length of < 2.5 standard deviations below the mean [1188,1200]. Micropenis should be distinguished from buried and webbed penis, which are usually of normal size. The length of the penis is measured on the dorsal aspect, while stretching the penis from the pubic symphysis to the tip of the glans [1188].

20.4. Diagnostic evaluation

20.4.1. The neonatal emergency

The first step is to recognise the possibility of DSD (Table 5) and to refer the newborn baby immediately to a tertiary paediatric centre fully equipped with neonatal, genetics, endocrinology and paediatric urology units. A diagnosis of a 46XX DSD as a result of congenital adrenal hyperplasia (the most common form of DSD) should not be delayed and represents a neonatal emergency situation due to the possibility of salt loss, which can be fatal.

Table 5: Findings in a newborn suggesting the possibility of DSD (adapted from the American Academy of Pediatrics)

20.4.2. Family history and clinical examination

A careful family history must be taken followed by a thorough clinical examination including various laboratory tests and imaging modalities (Table 6).

Table 6: Diagnostic workup of neonates with DSD

ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; hCG = human chorionic gonadotropin; LH = luteinising hormone; TST = testosterone; WES = whole exome sequencing.

A thorough and standardised clinical examination in a neonate presenting with ambiguous genitalia is important. In addition to an accurate description of the ambiguous genitalia, detailed information should be documented on the palpability and localisation of the gonads. Data gathered through the various examinations described below should help the team to come to a final diagnosis. Medical photography can be useful; however, this requires sensitivity and consent [1201].

Palpable gonad:
If it is possible to feel a gonad, it is most likely to be a testis. This clinical finding therefore virtually excludes 46XX DSD.

Phallus
The phallus length, phallus width and glans width should be measured. A cotton bud placed at the suprapubic base of the implant of the stretched phallus allows for a good measurement of phallic length.

Urogenital sinus opening
The opening of the urogenital sinus must be well-evaluated. A single opening must be identified, as well as a hymenal ring. Attention must be given to the fusion of the labioscrotal folds, as well as to whether they show rugae or some discolouration.

Ultrasound
Can help to describe the palpated gonads or to detect nonpalpable gonads [1197]. Mullerian structures, such as the vagina or utricular structures, can be evaluated as well [1202,1203].

Genitography
Can provide additional information on the urogenital sinus, especially on the exact position of the confluence. Moreover, genitography provides evidence of possible duplication of the vagina.

Invasive diagnostics
Can be helpful under general anaesthesia in some cases. During genitocystoscopy, the urogenital sinus, as well as the level of confluence, can be evaluated. Invasive diagnostics also allows also for evaluation of the vagina or utriculus - the possible presence of a cervix at the top of the vagina.

Laparoscopy
This is necessary to obtain a final diagnosis on the presence of impalpable gonads and on the presence of Mullerian structures. If indicated, a gonadal biopsy can be performed [1204,1205].

Genetics
Has an increasing role in the diagnostic process of DSD. Karyotyping is usually carried out at the beginning of the diagnostic process. Although next-generation sequencing-based molecular diagnostics and whole exome sequencing (WES) are becoming the gold standard for genetic evaluation, it may be difficult to prove variant causality or relate the genotype to the clinical presentation [1206].

These investigations will help to distinguish between various conditions of DSD and provide a rapid diagnosis of congenital adrenal hyperplasia (CAH).

20.5. Gender assignment

In the current climate, it goes without saying that open, honest, and complete communication with caregivers and eventually the affected person is mandatory. Educational and psychological support regarding the impact is needed for each individual to make sense of their condition, relate to their community and establish relationships. The lack of outcome data and different preferences make it challenging to determine whether and when to pursue gonadal or genital surgery. Shared decision-making is critical, combining expert healthcare knowledge and the right of a patient or caregivers to make fully informed decisions. This entails a process of education, sharing of risks/benefits, articulating the uncertainties in DSD care and outcomes, in addition to providing time for the patient and family to articulate back the risks and benefits of each option. The goal of all involved should be to individualise and prioritise each patient.

However, prior published adverse outcomes have led to recommendations to delay unnecessary surgery to an age when the patient can give informed consent. Surgery that alters appearance is not considered urgent. In 2017, the Parliamentary Assembly of the Council of Europe, the European Society for Paediatric Urology (ESPU), as well as the Societies for Pediatric Urology took a position in the debate on surgery for DSD [1189,1207,1208]. In an open letter to the Council of Europe, the European Society for Paediatric Urology expressed its attitude towards the above-mentioned resolution and concentrated on a worrying issue dealing with medicosurgical care for children with DSD. The letter stated that surgical interventions in children with DSD only being applied in emergency conditions is discordant with the definition of health according to the WHO, stating that health is not merely the absence of disease, but is a much broader concept, including physical, mental and social domains. This applies to children in particular, as favourable physical, social and emotional conditions are all critical factors for their optimal growth and development, which enables them to reach their full potential at an adult age. As social and emotional interactions with the parents or caregivers - being the most important adults in a young child’s life - form the basis for their future, treatment of children with DSD can best be organised in a patient- and family-centred, multidisciplinary setting, in an atmosphere based on openness, commitment and trust. Physicians, who each day treat children with a variety of congenital conditions - as do their parents or caregivers - are committed to the current as well as the future health and well-being of all children entrusted to their care. In contrast to what is alleged in the recommendation, parents and caregivers implicitly act in the best interest of their children and should be respected as their outstanding representatives and should not be put aside by claiming prohibition regulations regarding the well-informed decisions they make on their children’s behalf. Finally, in a published open letter, the ESPU advocate keeping dialogue open with the professionals active in specialised centres for multidisciplinary, patient- and family-centred care, as well as with patient societies, for which the present resolution is recognised as being a solid starting base [1209].

Genital surgery
The decision to proceed with genital surgery is acknowledged to be controversial. Patient-reported outcomes from adult patients who previously underwent early genital surgery demonstrate considerable variation, with perspectives dependent on, but not limited to, diagnostic category, gender, prior experience with surgical procedures, and contact with support groups [1210].

The majority of patients who have undergone surgery rated their appearance as satisfactory from an anatomical perspective. However, functional results were found to be less satisfactory due to the development of vaginal stenosis, or diminished sensation in the clitoris or the glans penis [1211]. Clinical decision-making with respect to genital surgery in patients with a DSD should not be made wantonly, but advisedly, in a patient and family-centred multi-disciplinary setting, on a case-by-case basis. These decisions should be supported and audited by improving information on long-term outcomes, informed consent and contact with support groups at both an individual and an institutional level.

20.6. Risk of tumour development

The dysgenetic gonads of individuals with DSD have an increased risk of developing germ cell neoplasia in situ (GCNIS), previously known as ‘carcinoma in situ,’ and overt germ cell cancer (GCC) as compared to the general population [1212]. The highest prevalence of GCC is seen in conditions characterised by disturbed gonadal development and in the presence of the Y chromosome or parts thereof (SRY- and GBY-encompassing regions) [1213]. In a large DSD-LIFE study, the overall prevalence of neoplastic lesions was 12%. Subanalysis demonstrated a significantly higher prevalence of 36% in patients with 46 XY gonadal dysgenesis as compared with other DSD subtypes [1214]. Conversely, patients with testosterone biosynthesis disorders and androgen action disturbances (46XY DSD group) have a much lower risk (1-15%) of GCNIS development during childhood and had a limited tendency towards invasive progression of the lesions. It has been hypothesised that a certain level of testosterone activity seems to be needed for GCNIS to progress to overt malignancy [1215,1216]. An overview of the risks of malignancy in different subtypes of DSD is shown in Table 7.

The issue of whether gonads should be removed and the timing of such surgery remains controversial and has been altogether questioned in some forms of DSD. Patients with, for example, CAIS benefit from the presence of testicles and the resultant aromatisation of the naturally occurring testosterone to oestrogens. The risk of malignant gonadal transformation in this subcategory is low (1.5%) with cases of malignancy first appearing after the second decade of life, thus allowing for the safe deferral of gonadectomy until after puberty [1216,1217]. This is, however, less clear for other subtypes of DSD and needs to be assessed for each case according to several factors such as patient age, underlying DSD subtype and especially the presence of a Y chromosome. In such cases, the location of the gonad, possible fertility, hormonal potential of the gonad and the possibility of gonadal monitoring together with surgical/anaesthesic risks incurred by gonadectomy should be taken into account [1190,1209]. In general, intra-abdominal gonads must be brought down to a superficial position or pexied to the abdominal wall to allow for monitoring, self-examination, and ultrasound-guided biopsies. High-risk gonads that fail to be brought down or streak-like gonads should be removed based on a risk- benefit analysis, and after appropriate interdisciplinary review [1190,1209]. Biopsies should be reviewed by an experienced pathologist and specialised immunohistochemistry is recommended for measurement of expressions of placental alkaline phosphatase (PLAP) and octamer-binding transcription factors 3 and 4, as it may be difficult to differentiate between GCNIS and delayed germ cell maturation in infants. Noninvasive markers such as serum microRNA (miRNA) for early-stage malignancy detection have been developed but have yet to be implemented in clinical practice [1190,1206].

Table 7: Risk of malignancy in various subtypes of DSD (Adapted from Looijenga et al., [1218])

PAIS = partial androgen insensitivity syndrome.

20.7. Quality of life

In general, adult patients with DSD report good QoL and physical health. However, there is an increased risk for both somatic and psychiatric morbidities [1219]. Moreover, a lower QoL was reported in the domain ‘social relationships’, which relates to personal relationships and sexual health [1220,1221]. In addition, patients with DSD report higher levels of psychological distress and mental health problems [1222,1223]. These elements should be included in the multidisciplinary and holistic health care for these patients.

A person’s experienced gender is a fundamental aspect of one’s sense of self. Gender incongruence can occur when there is incongruence between the physical and experienced gender and, if this causes significant distress, fulfils the criteria for the diagnosis gender dysphoria, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) of the American Psychiatric Association [1224]. Gender dysphoria is reported low in women with CAH, CAIS and complete gonadal dysgenesis favouring female sex of rearing. Gender dysphoria is reported high in females with 5α-reductase deficiency and 17β-Hydroxysteroid dehydrogenase-3 deficiency. Gender dysphoria is reported variable in PAIS or mixed gonadal dysgenesis [1225]. Approximately 3% of DSD patients undergo a gender change after puberty, which is a small group, but larger when compared to the general population [1226,1227].

20.8. Recommendations for the management of disorders/differences of sex development