Disorders of sex development and ambiguous genitalia

• A disorder of sex development (DSD) is any congenital condition in which chromosomal, gonadal or anatomical sex does not follow the usual male or female pathway; ambiguous genitalia in the newborn is the most visible presentation, but many DSDs declare themselves only in adolescence or adulthood.
• The first question in a newborn with ambiguous genitalia is whether the child is systemically unwell, because salt-wasting congenital adrenal hyperplasia (CAH) is the commonest dangerous cause and can kill within days if missed.
• The same baby can be reassuringly normal or dangerously ill depending on the karyotype and the gonad: a 46,XX infant with 21-hydroxylase deficiency has high androgens and a uterus; a 46,XY infant with the same enzyme defect looks like an unaffected boy but may salt-waste.
• Stepwise evaluation, not a single test, makes the diagnosis: visual inspection and score, urgent karyotype, 17-hydroxyprogesterone (17-OHP) and electrolytes, pelvic ultrasound, then a second tier of anti-Mullerian hormone (AMH), testosterone, dihydrotestosterone (DHT) and, where needed, an hCG stimulation test.
• Modern care is holistic, multidisciplinary and lifelong: sex assignment is a serious decision, not a reflex; counselling should begin early; and surgery with irreversible consequences is deferred whenever possible.

By the end of this page you should be able to:

1. Define DSD and classify it by karyotype, recognising that the 2006 consensus conference re-labelled what used to be called intersex conditions.
2. Examine a newborn with ambiguous genitalia systematically and calculate an external masculinisation score (EMS).
3. Decide which infants need investigation and which apparently isolated defects can be managed without a full DSD work-up.
4. Plan first-tier and second-tier investigations, explain what each result means, and recognise the commonest dangerous trap, salt-wasting CAH.
5. Explain the cross-check between 46,XX virilisation and CAH, including 21-hydroxylase deficiency versus 11-beta-hydroxylase and 3-beta-hydroxysteroid dehydrogenase deficiency.
6. Describe complete, partial and mild androgen insensitivity syndrome (AIS), their endocrine signature and management.
7. Outline the role of karyotype, AMH, the hCG stimulation test and urine steroid profiling in the work-up.
8. Discuss the consensus recommendations on multidisciplinary care, informed consent, genital surgery and transition to adult care.

A DSD is a congenital condition in which the usual process of sex determination or sex differentiation is altered, so that chromosomal, gonadal or anatomical sex does not follow the expected male or female pattern. The term replaced older, often pejorative labels such as pseudohermaphroditism and hermaphroditism when an international consensus conference re-labelled the field in 2006 (Lee et al, 2006, as summarised in Ahmed et al 2016 and Cools et al 2018). "Disorder" is itself debated; many people prefer "difference" of sex development, and both usages appear in the literature.

The most practical modern classification groups DSDs by karyotype, because karyotype is the one fact available to a clinician before any other investigation and it separates life-threatening CAH from other conditions immediately.

Two scoring systems help make the examination objective. The Prader score (stages I to V) describes how virilised a 46,XX CAH female's external genitalia are. The external masculinisation score (EMS, out of 12) adds up phallus size, labioscrotal fusion, site of the gonads and position of the urinary meatus; in one survey of healthy term newborn boys, 98 percent scored the maximum of 12, and only 1 in 423 scored below 11. A score below 11 in an infant is therefore a practical trigger for a formal DSD evaluation.

True genital ambiguity on expert examination is uncommon. The Society for Endocrinology UK guidance estimated that atypical genitalia may be seen in as many as 1 in 300 births, but a condition that produces genuine genital ambiguity on specialist examination may be as rare as 1 in 5000 births.^[1] CAH due to 21-hydroxylase deficiency is the single commonest cause and is found in about 1 in 14,000 to 1 in 18,000 births worldwide.^[4] Ovotesticular DSD is rarer still, accounting for roughly 3 to 10 percent of all DSD cases, and presents with ambiguous genitalia in about 90 percent of affected infants.^[5]

Geography matters. Well-organised newborn screening exists across the United States and many other countries, but not everywhere, so a male infant with salt-wasting CAH can still be missed until he collapses. Consanguinity raises the prevalence of all recessive forms, including 21-hydroxylase deficiency and the rarer enzyme defects.

DSD has many causes, grouped naturally into three mechanisms.

1. Excess androgen action on a 46,XX fetus. CAH is by far the commonest. Less commonly aromatase deficiency (in mother or placenta), or maternal androgen exposure from a tumour or drugs, can virilise the external genitalia.
2. Inadequate androgen action on a 46,XY fetus. This includes defects in testosterone synthesis (17-hydroxylase/17,20-lyase, 3-beta-hydroxysteroid dehydrogenase, 17-beta-hydroxysteroid dehydrogenase type 3, 5-alpha-reductase type 2), defects in the androgen receptor (CAIS, PAIS, MAIS), gonadal dysgenesis and Leydig-cell hypoplasia.
3. Chromosomal or gonadal mosaicism, producing ovotesticular or testicular DSD.

Risk factors include consanguinity, a family history of genital abnormalities, stillbirth, multiple miscarriage, infertility, hypospadias, hernia, cryptorchidism, delayed puberty or the need for steroid replacement. Maternal ill-health or drug exposure in pregnancy, intrauterine growth restriction and a history of low birthweight should also lower the threshold for investigation, especially in 46,XY DSD, because a mutation in the androgen receptor is more likely when birthweight is normal for gestation.

In the typical male embryo, the SRY gene on the Y chromosome drives the bipotential gonad to become a testis. Leydig cells then make testosterone, which stabilises the Wolffian ducts into male internal structures; conversion of testosterone to dihydrotestosterone (DHT) by 5-alpha-reductase type 2 virilises the external genitalia between roughly 8 and 14 weeks of gestation. Sertoli cells make anti-Mullerian hormone (AMH), which causes regression of the Mullerian ducts. In the typical female embryo, none of this happens, and the default pathway produces female internal and external structures.

DSD arises when one of these steps is disrupted.

• In 46,XX CAH, the fetal adrenal produces excess androgens, which act on the external genitalia of a genetic female: the clitoris enlarges and the labioscrotal folds fuse, sometimes producing a phallus and a single posterior (or perineal) opening. The uterus and ovaries are present because the adrenals do not make AMH. A 46,XX female with severe CAH is therefore "virilised" but has normal female internal anatomy; a 46,XY male with the same enzyme defect has no genital ambiguity at all but may salt-waste.
• In 46,XY gonadal dysgenesis, the testis never forms properly, so androgens and AMH are low: internal and external genitalia remain female or ambiguous and a uterus may be present.
• In AIS, testes and AMH are normal (so there is no uterus) but androgen action is impaired, producing a 46,XY baby with female or ambiguous external genitalia.
• In 5-alpha-reductase type 2 deficiency, testosterone is normal but DHT is low, so external virilisation is incomplete at birth but the child can virilise at puberty, because testosterone and its binding remain intact.
• In ovotesticular DSD, both ovarian and testicular tissue coexist, producing a mixed picture.

Ambiguous genitalia is the classic presentation, but the label is often applied too loosely. A newborn usually needs full evaluation when:

• the genitalia are truly ambiguous, so that sex assignment is not obvious;
• the appearance does not match any prior prenatal genetic test;
• there are apparently male genitalia with bilateral cryptorchidism, perineal or proximal (penoscrotal or scrotal) hypospadias, micropenis alone, or a combination of genital anomalies with an EMS below 11;
• there are apparently female genitalia with clitoromegaly, an inguinal hernia or mass, or labial fusion;
• the baby is systemically unwell or salt-wastes.

On examination, record the site of each gonad (scrotal, inguinal or impalpable), the degree of labioscrotal fusion, phallus size by measurement rather than appearance, and the true position of the urethral meatus, which may only be clear after surgery. Look for dysmorphic features, associated malformations and asymmetry: in roughly a quarter of infants, DSD is part of a wider syndrome.

DSD can first appear at puberty in three ways: a girl with primary amenorrhoea, with or without breast development; virilisation at puberty in someone raised female; or delayed puberty in an adolescent boy. Raised gonadotrophins, or an absent uterus on imaging in the presence of normal breast development, are indications for a karyotype. Clitoromegaly and hirsutism appearing at puberty in an amenorrhoeic girl point towards 17-beta-hydroxysteroid dehydrogenase type 3 deficiency or 5-alpha-reductase type 2 deficiency (Mullerian structures absent), or less commonly partial AIS; CAH and androgen-secreting tumours remain in the differential (Mullerian structures present).

The commonest practical errors are to treat CAH as a single diagnosis, and to assume that a normal-looking 46,XY baby cannot have a dangerous adrenal or gonadal disorder. The safety-first approach is therefore to screen every ambiguous infant for CAH before pursuing the androgen pathway.

In every infant with ambiguous genitalia or bilateral impalpable gonads, the first tier should define the sex chromosomes, delineate the internal genitalia by pelvic ultrasound, and exclude life-threatening CAH. That means:

• plasma glucose, serum electrolytes and creatinine;
• serum 17-OHP, ideally by liquid chromatography-tandem mass spectrometry, with norms stratified by gestational age where the local laboratory uses that approach;
• karyotype by PCR or FISH using X- and Y-specific markers, with results expected within one working day in a specialist centre, and a full karyotype to follow;
• pelvic and abdominal ultrasound looking for the uterus, gonads and adrenal enlargement, and for renal anomalies.

Two timing cautions matter. Serum 17-OHP is unreliable before 36 hours of age, and in salt-wasting CAH serum electrolytes often do not become abnormal before day 4. If CAH is strongly suspected and the baby is unwell, collect and store a second sample of sufficient volume for 17-OHP, testosterone, androstenedione and possibly renin activity or concentration, together with at least 5 mL of urine for a urine steroid profile, before starting treatment. Urine steroid profiling by gas chromatography-mass spectrometry confirms 21-hydroxylase deficiency and can identify the rarer CAH variants that also raise 17-OHP, such as 11-beta-hydroxylase and 3-beta-hydroxysteroid dehydrogenase deficiency.

Where newborn screening exists, a positive 17-OHP screen should be followed by referral to paediatric endocrinology and confirmatory testing as recommended by the Endocrine Society (Speiser et al 2018). The second-tier screen by liquid chromatography-tandem mass spectrometry has much better specificity than first-tier immunoassay, which is bedevilled by false positives in preterm and sick infants.

The pattern becomes informative quickly:

• 46,XX, no testes, uterus present, and markedly raised 17-OHP: CAH due to 21-hydroxylase deficiency is very likely.
• 46,XY with raised 17-OHP, low cortisol and salt-wasting: also 21-hydroxylase deficiency, despite normal male-looking genitalia.
• 46,XY with ambiguous genitalia but normal 17-OHP: move to the second tier and look for gonadal dysgenesis or a defect in androgen synthesis or action.

Where the first tier does not answer the question, measure:

• luteinising hormone (LH), follicle-stimulating hormone (FSH), testosterone, androstenedione, DHT and AMH;
• and, for hepatorenal or dysmorphic cases, an extended genetic panel.

AMH is made by Sertoli cells and is detectable at birth at much higher concentrations in boys than girls. Its interpretation (summarised in Ahmed et al 2016) is powerful:

The human chorionic gonadotrophin (hCG) stimulation test identifies functioning testicular tissue and biosynthetic defects in testosterone synthesis. Most UK protocols use intramuscular hCG 1000 to 1500 units on three consecutive days, sometimes followed by 1500 units on two days per week for a further two weeks. In a very young infant, the test may not be needed at all if serial blood samples show raised testosterone. A testosterone response is usually called normal if the absolute level reaches above the upper limit of the prepubertal range, or rises by more than twice the baseline. At a minimum, testosterone, DHT and androstenedione should be measured, on day 4 for the latter two.

Where AIS is a possibility, the endocrine signature is elevated or normal testosterone with high LH, normal FSH (regulated by inhibin rather than androgens) and elevated AMH in the newborn. Elevated AMH and testosterone together in a newborn both suggest androgen insensitivity and effectively exclude complete gonadal dysgenesis. During childhood, when the gonadotrophin axis is quiet, an hCG stimulation test is needed to assess Leydig cell function.

Urine steroid profiling and genetic testing follow. Genetic work-up used to have a low yield in 46,XY DSD, but targeted next-generation panels and whole-exome sequencing are becoming faster and cheaper. Targeted panels have the advantage of high-quality coverage of the genes of interest while reducing incidental findings, and a targeted regional panel can be complete in several weeks.

DSDs are diagnosed by tying together three strands: the karyotype, the gonadal histology or its biochemical surrogate, and the hormonal profile. There is no single score or cut-off. The UK first-tier criteria set out above (ambiguous genitalia, bilateral impalpable gonads, 46,XX with uterus and markedly raised 17-OHP indicating CAH) are the closest thing to a diagnostic algorithm, and they are supplemented by the EMS trigger of below 11.

Prader staging (I to V) remains the standard language for degree of virilisation in 46,XX CAH. The consensus recommendation is that Prader staging of the newborn genitalia not be used in isolation to make irreversible decisions, because it describes appearance, not cause or outcome.

The external masculinisation score (EMS) is a more objective, additive measure and is increasingly used in clinical and research settings.

The overriding principle is safety before diagnosis. A baby with ambiguous genitalia who is lethargic, hypoglycaemic, hyponatraemic or hyperkalaemic may have a salt-wasting crisis and should be treated as such while the evaluation proceeds. Treat as for adrenal insufficiency: intravenous hydrocortisone, fluid resuscitation and (in young infants) sodium chloride supplementation, following the CAH protocol, and collect the steroid samples before the first dose whenever feasible.

Psychological and communication principles matter from the first hour. The news should be given in a quiet setting, by a designated lead clinician, with repeated conversations and written material; the pace should be set by the family. Early referral to a specialist clinical psychologist is recommended for every newborn with DSD when sex assignment is delayed, and for adolescents at diagnosis or transfer.

Sex assignment should be avoided at birth wherever the genitalia do not allow a confident call, and should be undertaken by an experienced multidisciplinary team. The team, as a minimum, comprises paediatric endocrinology (usually the clinical lead), paediatric urology or surgery, clinical psychology, radiology, nursing, neonatology and clinical genetics, with links to adult endocrinology, gynaecology, genetics, clinical biochemistry, social work and, where possible, an ethics forum. The family chooses with the team; the final decision should follow a full discussion of what is known and what is uncertain.

Historically, CAH girls were raised female and early surgery was performed to "normalise" the genitalia. Current consensus (Cools et al 2018)^[2] and the Endocrine Society CAH guideline (Speiser et al 2018)^[4] have both moved towards shared decision-making: giving parents the option of delaying surgery until the child is old enough to participate; performing any surgery only in centres with experienced teams; and not equating CAH with rarer DSDs, since CAH carries a known, surgically addressable not-uncommon anatomy with specific long-term implications.

The child's gender identity should be established over time and not assumed from the karyotype. Gender identity in complete AIS is almost uniformly female, aligned with the sex of rearing; in PAIS it generally follows the sex of rearing, male or female; and in CAH it is usually but not always aligned with the sex of rearing.

Surgery has two broad purposes: to secure anatomy and function, and to manage gonadal risk.

• In all infants, urgent life-saving procedures come first: drainage of obstruction, salt-wasting treatment.
• In CAH females, surgeons discuss urogenital mobilisation and clitoroplasty for severe clitoromegaly, but the Endocrine Society (Speiser et al 2018) explicitly recommends informing parents of all options, including delaying surgery and observation, because high-quality long-term evidence for either early or late surgery is lacking.
• In AIS, the approach differs by phenotype (below).
• In ovotesticular DSD, the algorithm is gonadal biopsy first; one type of gonad is retained and the other excised, with genitoplasty tailored to the assigned sex.

Many in the patient and professional communities now argue that cosmetic genital surgery should not take place until the individual can consent. Several countries have moved towards legislative limits. Whether early or deferred surgery is better is not settled by good evidence, and audit through prospective registries remains the priority.

• Salt-wasting CAH infants need fludrocortisone and sodium chloride supplements, and growing children hydrocortisone (not long-acting potent glucocorticoids), with increased doses for fever above 38.5 degrees Celsius, dehydration or major surgery, but not for everyday emotional stress.
• Children and adolescents with AIS or gonadal dysgenesis who are gonadectomised need sex-steroid replacement: oestrogen started in low doses at 9 to 11 years in those raised female, or high-dose testosterone trials in those raised male with PAIS.
• Adults with DSD need transition to an adult multidisciplinary service, continued hormone replacement, fertility counselling and bone and metabolic follow-up.
• Gonadal retention carries a germ-cell tumour risk that varies with the degree of gonadal differentiation: highest in early gonadal dysgenesis (SRY and WT1 disorders), intermediate in 45,X/46,XY dysgenesis, and comparatively low in AIS. Where gonads are retained, periodic surveillance with ultrasound (or MRI for abdominal gonads) is usual.

CAH due to 21-hydroxylase deficiency must be excluded before any other diagnosis is pursued. The reasoning is simple and safety-critical: it is the commonest cause of ambiguous genitalia, it is treatable, and missing the salt-wasting form can be fatal in the first two weeks.

21-hydroxylase converts 17-OHP to 11-deoxycortisol and progesterone to deoxycorticosterone. When it is deficient, cortisol and (in severe cases) aldosterone fall, ACTH rises and cortisol precursors are diverted to androgen synthesis. Severity depends on how much enzyme activity remains.

• Classic salt-wasting form: severe enzyme loss. 46,XX newborn females have variable virilisation of the external genitalia; 46,XY males have normal male genitalia but become hyponatraemic, hyperkalaemic and hypovolaemic in the first one to two weeks. Newborn screening exists to catch these boys.
• Simple virilising form: partial deficiency. Both sexes virilise; girls have ambiguous genitalia, boys have early growth and penile enlargement.
• Non-classic form: mild deficiency. Presents later with premature pubarche, hirsutism, acne, anovulation or infertility; cortisol synthesis is usually adequate, so Addisonian crises do not occur.

The Endocrine Society (Speiser et al 2018) reminds clinicians not to equate CAH with the rarer DSDs when formulating management, because CAH is a single, well-understood enzyme defect with a specific treatment.

The other two enzyme defects that can also raise 17-OHP and virilise a 46,XX newborn are:

• 11-beta-hydroxylase deficiency, which also causes hypertension from excess deoxycorticosterone: ambiguous genitalia in a 46,XX infant, hypertension in older children, different steroid profile on urine testing.^[1]
• 3-beta-hydroxysteroid dehydrogenase deficiency, which affects both sexes and often presents as salt-wasting.

In a 46,XX infant, the combination of "virilised female plus medical urgency of salt wasting" points to these three enzyme defects and is excluded primarily by the 17-OHP level, the electrolyte panel and the blood pressure. In a 46,XY infant, the defect is not visible in the genitalia at all, which is precisely why markers and screening are needed.

Screening for CAH is recommended for all newborns by the Endocrine Society (Speiser et al 2018): first-tier 17-OHP assays stratified by gestational age, with a second-tier test by liquid chromatography-tandem mass spectrometry to reduce false positives. For infants with ambiguous genitalia, referral to a paediatric endocrinologist and confirmatory 17-OHP testing (with, where equivocal, a cosyntropin stimulation test) is the established pathway.

AIS is an X-linked condition and the commonest molecular diagnosis in newborns with 46,XY DSD. It results from mutations in the androgen receptor gene, leading to complete or partial resistance to androgens despite a 46,XY karyotype and normally formed testes.

The clinical spectrum is:

• Complete AIS (CAIS). Normal female external genitalia. The baby may present antenatally (46,XY karyotype with female-looking genitalia on scan), in childhood (an inguinal hernia in a girl), or after puberty (primary amenorrhoea). Breasts develop because oestrogen from aromatised androgens acts unopposed; pubic and axillary hair are sparse or absent; there is no uterus and a short, blind-ending vagina. CAIS prevalence in 46,XY males is estimated at 1 in 20,400 to 1 in 99,100.
• Partial AIS (PAIS). Atypical genitalia at birth in a 46,XY infant, ranging from proximal hypospadias to micropenis. Gynaecomastia at puberty often finally reveals the diagnosis.
• Mild AIS (MAIS). Normal male genitalia, presenting in adolescence or adulthood with gynaecomastia, infertility or sometimes with bulbar and muscular atrophy as in Kennedy disease.

Endocrine features, according to Batista et al (2018)^[3], are the classic picture of androgen resistance: LH and testosterone elevated (or at least normal) with high AMH in the newborn; FSH usually normal because it is driven mainly by inhibin. Gonadal tumour risk is low in CAIS and higher in PAIS (up to about 15 percent), mainly because residual androgen responsiveness in PAIS seems to preserve germ cells.

Management follows the phenotype:

• CAIS. Gonadal retention into adolescence allows spontaneous breast development; oestrogen replacement starting at 11 to 12 years if gonadectomy has been performed earlier. The Endocrine Society-era consensus and patient-centred practice increasingly favour delaying gonadectomy until late adolescence, with tumour surveillance, to allow spontaneous puberty. Non-surgical vaginal dilation after puberty is preferred to vaginoplasty.
• PAIS raised male: cryptorchidism and hypospadias corrected in early childhood; high-dose testosterone trials at puberty, with cosmetic correction of gynaecomastia.
• PAIS raised female: gonadectomy in childhood, genitoplasty where needed, oestrogen replacement from puberty.
• MAIS: gynaecomastia surgery if required; evaluation of infertility.

Gender identity is strongly aligned with sex of rearing in both CAIS and PAIS.

The single most useful way to approach a DSD in a newborn is to think in tiers and to follow the laboratory, not the appearance, of the gonads.

Several interpretive points are worth memorising:

1. A 46,XX karyotype with a uterus and markedly raised 17-OHP makes CAH (usually 21-hydroxylase deficiency) very likely; the cause is enzymatic, not chromosomal.
2. In an apparently male newborn, a normal-looking 21-hydroxylase-deficient baby has the same adrenal risk without any clue on inspection: only the newborn screen protects him.
3. Increased AMH above the male range suggests either AIS, 5-alpha-reductase deficiency, a testosterone biosynthesis defect or Leydig-cell hypoplasia: the testes are present, producing AMH, but androgen action is impaired.
4. An absent uterus in a 46,XY individual implies functioning Sertoli cells and normal AMH, so the defect is post-biosynthetic (AIS) or a synthesis block after 8 weeks.
5. LH is raised and FSH usually normal in AIS, because the androgen negative feedback loop is disrupted while inhibin feedback on FSH is preserved.
6. The hCG test is invasive and should be reserved for the second tier, after discussion with the regional team.
7. During the first 100 days, testosterone and DHT fluctuate markedly in boys; interpretation must use age-, sex- and method-appropriate reference intervals, and close collaboration between clinician and clinical biochemist is essential.

Nomenclature and management in DSD rest on two landmark documents, and the newest open-access edition of each is worth knowing by name.

• The International Consensus Conference on Intersex, Chicago 2006, introduced the term DSD and laid down the principles of multidisciplinary, holistic care (Lee et al 2006, as summarised in Ahmed et al 2016).
• Caring for individuals with a difference of sex development: a consensus statement (Cools et al, Nature Reviews Endocrinology 2018), from the European COST Action BM1303 network, is the most recent international consensus on diagnosis, multidisciplinary care, transition, tumour risk, surgical outcomes, and long-term follow-up.
• Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015, published Clin Endocrinol 2016) is the most detailed, practical source for first- and second-tier investigation, AMH interpretation and the hCG stimulation protocol.
• Endocrine Society clinical practice guideline: Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency (Speiser et al, Journal of Clinical Endocrinology and Metabolism 2018) underpins the CAH cross-check, screening, genotype and management sections above.

Where these sources differ in emphasis, the disagreement is real and worth stating plainly. The UK guidance (2016) is prescriptive about initial investigation timelines and laboratory thresholds; the 2018 consensus statement is broader, more psychosocial, and more cautious about irreversibility; and the Endocrine Society (2018) treats CAH as a distinct condition with its own evidence-based recommendations. Scientifically rigorous, long-term outcome data on almost every contentious question, especially the timing of genital surgery, remain scarce, and several recommendations in all of these documents are consensus-based rather than evidence-graded.

Complications follow the mechanism and the age of diagnosis.

• Salt-wasting crisis in untreated CAH, with hypovolaemia, hyponatraemia, hyperkalaemia and death.
• Masculinisation-related urinary difficulties, clitoromegaly, and the physical and psychosocial consequences of virilisation in 46,XX CAH.
• Infertility in almost all forms of DSD, with only rare exceptions (a single reported PAIS fertility after prolonged testosterone therapy).
• Germ-cell tumour risk: low in CAIS, around 15 percent in PAIS, and highest in early gonadal dysgenesis.
• Impaired sexual quality of life and (in some, but not all) psychological distress, particularly around identity, disclosure, appearance and fertility.
• Complications of treatment itself: over- or under-replacement with glucocorticoids; osteoporosis; metabolic syndrome from chronic over-treatment; vaginoplasty stenosis or fistula.

With good care, the prognosis for life is good. Newborn screening has dramatically reduced mortality in salt-wasting CAH. Long-term outcomes however depend heavily on diagnostic accuracy, quality of multidisciplinary follow-up, timing and quality of surgery where applicable, and on the specific condition: CAH is a fully treatable chronic disease, AIS is a hormone-resistance syndrome requiring lifelong follow-up, and the gonadal dysgenesis disorders carry the highest tumour and fertility risks. Many studies report on techniques or protocols that are no longer in use, so the evidence base for long-term outcomes is weaker than clinicians would like and several areas, especially ageing with a DSD, remain under-studied.

• CAH: universal newborn screening, ideally by 17-OHP first tier and confirmatory LC-MS/MS second tier, is recommended.
• Early recognition of DSD: careful newborn examination, with an EMS or Prader score and a low threshold for genetics referral when additional anomalies coexist.
• Prenatal: non-invasive fetal sex determination is routine; prenatal treatment of CAH remains experimental and is restricted to formally approved protocols.
• Family support and genetic counselling, including for relatives of an affected child and for future pregnancies, should be offered and repeated at transition.

Age, sex and phenotype interact in ways that make them hard to disentangle.

• Infants: stabilise, then investigate; CAH screening protects the boys, who have nothing to find on examination.
• Children with CAH: monitoring of growth, blood pressure, bone age and biochemistry; avoidance of adult-type surgeries before discussion.
• Adolescents: three presentations (amenorrhoea, virilisation, delayed puberty); psychological input mandatory; transition planning should start years early.
• Families and social context: disclosure should be age-appropriate, repeated and supported; peer support and specialist psychology improve outcomes.
• Low-resource settings: a transthoracic ultrasound and a basic hormone panel are usually available; urine steroid profiling and extended genetics may not be. The first-tier approach (glucose, electrolytes, 17-OHP, karyotype, ultrasound) should be completed before any surgery, and referral to a regional or international centre is strongly advised for complex cases. If CAH is suspected and the baby is unwell, do not wait for confirmatory testing before starting life-saving treatment, and collect urine for a steroid profile before the first dose.
• Immunocompromised and pregnant patients are managed with the same hormonal groups; drug contraindications and stress-dose rules follow standard guidance for adrenal insufficiency.

• DSD is an umbrella for a heterogeneous group of conditions; classifying by karyotype is the most practical first step.
• True genital ambiguity on expert examination is about 1 in 5000 births; atypical genitalia of any degree about 1 in 300.
• CAH due to 21-hydroxylase deficiency is the commonest cause: 1 in 14,000 to 1 in 18,000 births, with 46,XX virilisation and invisible salt-wasting in 46,XY males.
• Every ambiguous newborn should have glucose, electrolytes and 17-OHP measured in the first tier, plus karyotype and pelvic ultrasound to look for a uterus.
• A 46,XX karyotype with a uterus and markedly raised 17-OHP makes CAH due to 21-hydroxylase deficiency very likely.
• AMH tells you whether testicular tissue is present and active; above the male range points to AIS, 5-alpha-reductase deficiency or a biosynthetic defect.
• The hCG stimulation test belongs to the second tier and always to an experienced team.
• AIS is X-linked, caused by androgen receptor mutations, and ranges from CAIS (female phenotype, no uterus) through PAIS to MAIS; phenotype is not reliably predicted from genotype.
• CAIS and PAIS share high LH and testosterone with normal FSH; newborns with AIS have raised AMH and testosterone.
• Do not rush to assign a sex or to operate: lifetime outcomes are uncertain, and delayed, shared decision-making is the current consensus.
• Multidisciplinary care, and transition to adult services, are not optional extras; they are the model on which outcomes depend.
• Ovotesticular DSD accounts for about 3 to 10 percent of all DSD cases and is diagnosed on histology, not on appearance alone.

• Congenital adrenal hyperplasia
• Cryptorchidism
• Hypospadias and congenital malformations
• Puberty and sexual development
• Chromosomal disorders in childhood
• Hypothyroidism and other endocrine presentations
• Gonadal tumours and testicular cancer
• Adrenal insufficiency
• Neonatal jaundice
• Prematurity and its complications

This topic was reviewed against the open-access sources listed in the front matter; access dates are 2026-10-31.