Terminology

Such disorders used to be called intersex disorders but a new terminology has arisen by consensus which recognises advances in molecular genetics as well as consideration of the attendant management and ethical controversies.^[4][5]

Controversial and pejorative terminology such as 'pseudohermaphroditism' and 'hermaphroditism' has been discarded with the help of pathophysiological insights. Previously unclassifiable conditions (such as penile agenesis and cloacal exstrophy) are included. The term 'disorders of sex development' is now used to indicate congenital conditions with atypical development of chromosomal, gonadal or anatomical sex. Some of the old terminology will be used to highlight changes in terminology.

Normal sexual determination and differentiation

Management and diagnosis of disorder of sex development (DSD) requires understanding of normal sexual determination and differentiation.^[1] Chromosomal sex prescribes gonadal sex which in turn prescribes the phenotypic sex. The gonad type determines whether the Müllerian or Wolffian ducts develop or regress. Gender identity is affected by prenatal and postnatal brain development and not just by phenotypic appearance.

• Male and female embryos develop in a similar manner until 6-7 weeks of gestation.
• In the presence of a Y chromosome the undifferentiated gonad develops into a testis and, in the absence, it develops into an ovary. The genetic information for this to happen is held on the short arm of the Y chromosome - the sex-determining region Y (SRY). In the absence of this region, the gonad develops into an ovary. However, other genes are important, as demonstrated by the existence of XX males with testicular tissue without the SRY.
• The primitive gonad develops from primordial germ cells from posterior endoderm of the yolk sac.
  • With Y chromosome, primitive seminiferous tubules develop in the centre of the gonad. Fetal pituitary luteinising hormone (LH) and placental human chorionic gonadotrophin (hCG) encourage fetal Leydig cells to develop and produce testosterone.
  • In the absence of a Y chromosome the germ cells undergo mitotic and meiotic divisions to form oocytes. These become surrounded by a layer of granulosa cells and are called primordial follicles. These are some 7 million in number at the 20th to 25th week of gestation. With the surge of fetal pituitary follicle-stimulating hormone (FSH) the first primary follicles are formed.
• Differentiation of genital ducts.
  • Around the 4th week of gestation, 2 substances - testosterone and anti-Müllerian hormone (AMH) - are critical for male differentiation of the genital ducts. The testosterone induces primordial Wolffian (mesonephric) duct to become epididymis, vas deferens and seminal vesicle. High local levels of testosterone are needed to achieve this. AMH is produced by Sertoli cells of the testis and this suppresses passive development of Müllerian ducts (into the upper third of the vagina, uterus and Fallopian tubes). Testosterone may enhance the AMH inhibition.
  • In females, the Wolffian ducts disappear and the Müllerian ducts develop into the upper third of the vagina, uterus and Fallopian tubes. Exposure to androgens does not affect this and neither does the presence or absence of ovaries.
• Differentiation of external genitalia. The external genitalia of males and females are identical in the first 7 weeks of gestation.
  • In males, from 7 weeks active differentiation towards the male phenotype occurs moderated by testosterone and its conversion to dihydrotestosterone (DHT) by 5 alpha reductase (present in the cells of external genitalia and urogenital sinus). Genital tubercle becomes glans. Fusion of urethral folds and groove forms the shaft of the penis. Labioscrotal swellings fuse and enlarge to become scrotum.
  • In the female, genital tubercle becomes the clitoris, labioscrotal swellings the labia majora and urethral folds the labia minora. The urogenital sinus forms the lower two-thirds of the vagina.
• Testosterone-related development begins at 6 weeks' gestation, coinciding with a surge in LH but, after about 14 weeks, testosterone levels are dependent on placental hCG. The consequent fetal levels of testosterone help the growth of the phallus and scrotum, and testicular descent. Micropenis and cryptorchidism result from congenital gonadotrophin deficiency.

Epidemiology

Disorders of sex development (DSDs) are caused by a variety of different conditions which vary greatly in incidence:

• Genital anomalies are estimated to occur in 1 in 4,500 births.^[6]
• The most common cause of ambiguous genitalia in the newborn is congenital adrenal hyperplasia (CAH) - 1 per 15,000 live births.^[3][7] CAH appears to be more common in those of European Jewish, Hispanic, Slavic and Italian descent.
• Mixed gonadal dysgenesis (MGD) is the next most common cause of ambiguous genitalia.
• Hypospadias is quite common (1 in 300 live births) but this is combined with undescended testes in less than 1% of such cases. It is estimated that 50% of infants with hypospadias and unilateral or bilateral cryptorchidism will have a disorder.^[3][8]

  The pathophysiology and classification of disorders of sex development

  To make a diagnosis it is essential not only to understand normal development but also to understand the different pathophysiological mechanisms responsible for disorders of sex development (DSDs).
  
  Different classifications have been used in the past.

  Old terminology

  The traditional classification of so-called intersex conditions put more emphasis on the presenting features:
  • Female pseudohermaphrodite (2 ovaries). 46XX karyotype, normal ovaries and female internal genitalia with varying degrees of external virilisation (CAH is the most common cause and different enzyme defects are responsible).
  • Male pseudohermaphrodite (2 testes). 46XY karyotype and testes but inadequate masculinisation of either genital ducts or external genitalia or both. This is caused by deficiency of Müllerian-inhibiting substance (MIS), deficient testosterone biosynthesis, androgen insensitivity and 5 alpha reductase deficiency.
  • True hermaphrodite (ovary and/or testes and/or ovotestis). This is uncommon as a cause of ambiguous genitalia (10% of cases).
  • Mixed gonadal dysgenesis (testis plus streak gonad).
  • Pure gonadal dysgenesis (bilateral streak gonads).

  New terminology

  The old classification and terminology have been deemed unhelpful to management by many and abandoned in favour of a classification which not only highlights the underlying pathophysiology but which avoids pejorative terminology.^[2]
  • Virilised females:
    • Virilisation by androgens of fetal origin. This may be from congenital adrenal hyperplasia (CAH) or persistent fetal adrenocortical steroids.
    • Virilisation by androgens of maternal origin. These may be from drugs (anabolic steroids, testosterone, danazol, progestogens, etc.), tumours (ovarian or adrenal) or maternal CAH.
    • Dysmorphic syndromes (eg Beckwith-Wiedemann syndrome, Seckel's syndrome, Zellweger's syndrome).
    • Local abnormalities (eg lipomas, neurofibromatosis).
    • Idiopathic.
  • Inadequately virilised males:
    • Leydig cell agenesis or hypoplasia.
    • LH deficiency.
    • Inborn errors of testosterone biosynthesis. These may affect testes and adrenal glands (eg cholesterol side chain cleavage deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency, 17 alpha-hydroxylase deficiency) or just testes (eg 17,20-lyase deficiency).
    • Target tissue defects. This includes defects in testosterone metabolism (eg 5 alpha reductase deficiency) or androgen receptor defects.
    • Persistent Müllerian duct syndrome. Anti-Müllerian hormone (AMH) deficiency will cause this.
    • Dysmorphic syndromes such as Dubowitz's syndrome, Smith-Lemli-Opitz syndrome, etc.
  • Disorders of gonadal differentiation. The role of the testis in development of internal and external genitalia means that dysgenetic gonads produce combinations of abnormalities of internal and external genitalia. Examples include:
    • Gonadal dysgenesis. Patients often have XO (often with mosaicism, eg Turner's syndrome) or XY karyotypes and present as females with amenorrhoea.
    • Mixed gonadal dysgenesis. Patients may typically have testes palpable (inguinal or scrotal) with perineal hypospadias. On the side of testes (ipsilateral) Wolffian structures, absent Müllerian but Müllerian and absent Wolffian same side as streak gonad.
    • 'Vanishing testes syndrome' or anorchia. Boys presenting with normal male genitalia and bilateral cryptorchidism, who must have had testicular function in the fetal period.
    • True hermaphrodites. Well-developed ovarian and testicular tissues are found in either the same or opposite gonads. Genital duct development is according to the ipsilateral gonad. Can present with ambiguous genitalia or at puberty.

  Presentation

  The possibility of disorders of sex development (DSDs) constitutes a neonatal emergency and requires immediate referral to an experienced multidisciplinary team (MDT), accompanied by kind and clear explanation to parents. Naming and registration of such infants should be delayed for as long as possible.^[9]
  Common findings in the newborn suggesting a DSD:^[9]

  • Male appearance but with associated abnormalities of genitalia:
    • Severe hypospadias with bifid scrotum.
    • Undescended testis/testes with hypospadias.
    • Bilateral non-palpable testes in a full-term apparently male infant.

  • Female appearance but with associated abnormalities of genitalia:
    • Clitoral hypertrophy of any degree, non-palpable gonads.
    • Vulva with single opening.

  • A baby with indeterminate sex where it is impossible to identify as male or female immediately:
    • Ambiguous genitalia.
  Team effort is required in diagnosis and this begins with taking time to take a detailed history. Diagnosis should follow an orderly process and jumping to conclusions should be avoided.^[2] The most commonly seen condition will be the virilised 46,XX female with congenital adrenal hyperplasia (CAH) and often the challenge is to identify less common causes. There is a strong possibility of misdiagnosis and gender misassignment, particularly with CAH, where virilisation can be extreme.

  History

  The history should incorporate maternal, family and neonatal history:
  • Maternal:
    • Medication history including any exposure to androgens.
    • Any history or signs of virilisation in the mother.
    • A history of unexplained early or neonatal deaths may indicate missed adrenogenital deficiency.^[10]
    • Any history of a disorder of sex development (DSD) in other children.^[10]
    • A history of parental consanguinity.
  • Family history suggesting a genetically transmitted trait - for example, of:
    • Ambiguous genitalia
    • Infertility
    • Primary amenorrhoea
    • Late puberty
    Recessive traits will tend to occur in siblings, and X-linked abnormalities will be seen in males scattered across the family tree.
  • Neonatal history of failure to thrive, vomiting or diarrhoea.

  Examination

  Broadly, this should include:
  • A search for other congenital abnormalities.
  • Identification of dysmorphic features.
  • Looking for increased pigmentation of the genital and areolar area (adrenogenital syndrome).
  • Careful examination of the external genitalia (size of phallus, degree of differentiation, eg Prader stages, clitoromegaly, hypospadias, position of meatus). Labioscrotal folds may be fused to give the appearance of a scrotum and be rugose or pigmented in adrenogenital syndrome.
  • Examination of gonads. Careful examination of the labioscrotal folds, which usually identifies testicular material although ovotestes may descend as well. The inguinal regions should also be carefully examined for gonads.
  • Rectal examination which may identify cervix and uterus.
  • Measurement of blood pressure.

  Investigations

  Work-up may include a variety of tests. In practice one of the most important is pelvic ultrasound. If a uterus is present, the baby is almost certainly a virilised female and most likely to have congenital adrenal hyperplasia (CAH). If the uterus is absent, the diagnosis is likely to be more difficult.
  • Laboratory studies:
    • Chromosomal analysis for karyotype. Rapid karyotyping from buccal smears takes less than 24 hours as compared to 5 days for chromosome analysis.
    • Endocrine screening:
      • Testosterone, androstenedione, dihydrotestosterone (DHT), dihydroepiandrosterone (DHEA), 17 alpha-hydroxyprogesterone.
      • Luteinising hormone (LH), follicle-stimulating hormone (FSH).
      • Adrenocorticotropic hormone (ACTH), renin, aldosterone, etc.
    • Electrolytes, urea and creatinine.
    • Androgen receptor levels.
    • 5 alpha reductase levels.
  • Imaging:
    • Pelvic/renal/bladder ultrasound. Adrenal glands may be seen to be enlarged. Virilisation with a uterus makes CAH likely.
    • Genitography. This helps define ductal anatomy.
    • CT and MRI scanning are not usually necessary but can further help identify anatomy.
  • Other procedures include laparotomy or laparoscopy with or without gonadal biopsy. This can differentiate ovaries, testes, ovotestes and streak gonads.
  • Urine tests for steroid excretion, stimulation tests and other invasive tests are rarely needed.

  Diagnosis

  • This should be made with great care and after proper diagnostic work-up.^[1] Despite thorough investigation, definite final diagnosis cannot always be made.^[7]
  • Referral and consultation between specialties (for example: gynaecology; urology; endocrinology; genetics; surgery; psychiatry) are often important.^[2][3]

  Differential diagnosis

  The range of possibilities is considerable and can be appreciated from the classification of the causes of disorders of sex development (DSDs).

  Management

  Prompt referral is essential.

  Gender assignment

  • Parents should be advised to delay registering the birth (it can be legally difficult to alter later) and naming the baby, until the sex of rearing is decided.
  • This should be done after completion of the diagnostic process, including full clinical, genetic and biochemical investigation.
  • It should be done without delay and undue haste.
  • It should be done involving the parents in full discussion and explanation.
  • The assignment should aim to offer the best opportunity for normal puberty and sex life with unambiguous, functionally normal external genitalia and occasionally reproductive capability.
  When considering the male gender, the size of the penis is important but so is the potential to grow. It is important to establish the potential for growth with a trial of testosterone. Finding out later (at puberty) that androgen insensitivity prohibits masculinisation is to be avoided. It is important to identify virilised females, particularly where virilisation is extreme, as it can be for example in congenital adrenal hyperplasia (CAH).
  
  Full discussion and explanation of the diagnosis often avoids medicolegal difficulties.^[3] There is controversy surrounding gender assignment, particularly where genital surgery is involved. In the USA, intersex activists have called for a moratorium on gender assignment until long-term studies (eg North American Task Force on Intersexuality) have been completed. It has been said that the most important sex organ is the brain.^[3] Certainly gender identity disorders and gender dysphoria require highly specialised and sensitive management, howsoever they become manifest.^[11]

  Emergency treatment

  CAH can present with adrenocortical crisis, hyponatraemia or hypoglycaemia, and emergency treatment of these complications is required.^[7] Monitoring for this (eg weight, potassium, glucose) is important.^[2]

  Long-term management

  As well as achieving early diagnosis and emergency treatment of complications, there are longer-term aspects to management which will vary according to the condition. CAH requires long-term care for example.
  • Medical care. Supplemental hormone therapy may be required if gonadal function is inadequate.
  • Surgical treatment may be required. The timing of surgery can be controversial.^[9] Examples of the requirement for surgery include:^[9]
    • Hypospadias in males.
    • Vaginoplasty and clitoroplasty, which may be required In virilised females.
    • Gender reassignment, which may require surgery (multiple procedures).
    • Gonadectomy, which may be advisable for patients with dysgenetic or nonfunctional gonads because of the risk of malignant change.
  • Psychological support. Families will need intensive support, full explanations and information. This helps bonding with their child and probably the development of the child.