Disorders of Sex Development and Klinefelter Syndrome

Disorders (differences) of sex development are congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. They affect about 1 in 4,500 births for ambiguous genitalia, and up to 1 in 1,000 to 1 in 200 if all variations are included.

Normal sex differentiation

• Chromosomal sex is determined at fertilisation. SRY on the Y chromosome (with SOX9, SF1/NR5A1, WT1) drives testis formation by week 7. Sertoli cells secrete anti-Müllerian hormone (AMH), which regresses Müllerian structures. Leydig cells secrete testosterone (stimulated by hCG then LH), which maintains Wolffian ducts (epididymis, vas, seminal vesicles). Dihydrotestosterone, formed by 5-alpha reductase type 2, virilises the external genitalia and prostate. Insulin-like 3 (INSL3) mediates transabdominal testicular descent.
• In the absence of SRY and androgens, ovarian development and female internal and external structures follow.

Classification (Chicago consensus 2006 and updates)

• 46,XX DSD:
• Disorders of ovarian development (ovotesticular DSD, testicular DSD from SRY translocation, SOX9 duplication).
• Androgen excess: congenital adrenal hyperplasia (21-hydroxylase deficiency, most common cause of ambiguous genitalia, 11-beta-hydroxylase and 3-beta-HSD deficiency), aromatase deficiency, P450 oxidoreductase deficiency, fetal or maternal sources (luteoma, drugs).
• Müllerian anomalies (MRKH syndrome).
• 46,XY DSD:
• Disorders of testis development (complete and partial gonadal dysgenesis: Swyer syndrome, SRY, SF1, WT1 mutations: Denys-Drash and Frasier syndromes).
• Disorders of androgen synthesis or action: Leydig cell hypoplasia (LHCGR), 17-beta-hydroxysteroid dehydrogenase 3 deficiency, 5-alpha reductase 2 deficiency, StAR and CYP11A1 defects, androgen insensitivity syndrome (complete, partial, mild; AR gene), and AMH or AMH receptor defects (persistent Müllerian duct syndrome).
• Others: severe hypospadias, cloacal exstrophy.
• Sex chromosome DSD: Klinefelter (47,XXY), Turner (45,X), mixed gonadal dysgenesis (45,X/46,XY), and chimerism (46,XX/46,XY).

Klinefelter syndrome

• The commonest sex chromosome aneuploidy and genetic cause of male hypogonadism and infertility, affecting about 1 in 600 males, but 60 to 75% are undiagnosed.
• Mechanism: nondisjunction in parental meiosis (maternal age raises risk, paternal origin in about half). Mosaic forms (46,XY/47,XXY) have a milder phenotype, and variants include 48,XXXY and 48,XXYY.
• Pathophysiology: progressive seminiferous tubule hyalinisation and fibrosis from puberty, with Sertoli cell and germ cell loss, low inhibin B, high FSH, and eventual Leydig cell insufficiency with testosterone decline.
• Associated risks: osteoporosis, metabolic syndrome and type 2 diabetes, venous thromboembolism, autoimmune disease (SLE, Sjögren, rheumatoid arthritis, thyroid disease), breast cancer (20 to 60 times men with 46,XY), extragonadal germ cell tumours (mediastinal), and learning, language and attention disorders.

Disorders of sex development

• Neonates: ambiguous genitalia, apparent female genitalia with inguinal masses, apparent male genitalia with bilateral impalpable gonads, severe hypospadias (proximal, with undescended testes), micropenis, clitoromegaly, fused labia, and discordance between prenatal karyotype and genital appearance. This is a medical and social emergency needing careful, non-assumptive communication.
• Salt-wasting crisis (congenital adrenal hyperplasia): at 1 to 3 weeks, with vomiting, poor feeding, dehydration, hyponatraemia, hyperkalaemia, hypoglycaemia and shock.
• Puberty: primary amenorrhoea (complete androgen insensitivity, with normal breasts but sparse or absent pubic and axillary hair; Swyer syndrome with absent puberty; MRKH with normal secondary sex characteristics), virilisation at puberty of a child raised as a girl (5-alpha reductase 2 deficiency, 17-beta-HSD3 deficiency), delayed puberty, and unexpected breast development in a boy.
• Adults: infertility, inguinal hernia containing gonads or Müllerian structures, gonadal tumours (gonadoblastoma, dysgerminoma, risk highest in Y-containing gonadal dysgenesis and intra-abdominal gonads, 15 to 35%).

Klinefelter syndrome by age

• Infants and children: hypotonia, language delay, learning difficulties, small penis or cryptorchidism, tall stature from mid childhood.
• Adolescents: tall stature with long legs, eunuchoid proportions, small firm testes (volume under 4 to 6 mL), incomplete virilisation, gynaecomastia (50%), low libido, behavioural issues (anxiety, ADHD, autism features).
• Adults: infertility (azoospermia in about 90%), hypogonadism, erectile dysfunction, osteoporosis, central adiposity, metabolic syndrome, varicose veins, leg ulcers, and psychosocial difficulties. Diagnosis often follows fertility evaluation.

Red flags: neonatal adrenal crisis, unilateral palpable gonad with a contralateral impalpable gonad, hypospadias with cryptorchidism, virilisation in a girl, and hypertension (11-beta-hydroxylase deficiency, 17-alpha-hydroxylase deficiency).

Newborn with ambiguous genitalia (urgent, multidisciplinary)

• Do not assign sex in the delivery room. Examine for gonads, phallus length, urethral opening, and labioscrotal fusion (Prader staging 1 to 5, external masculinisation score).
• First-line tests: karyotype (rapid FISH for X and Y/SRY within 24 to 48 hours), electrolytes and glucose (repeat daily for the first 2 weeks), 17-hydroxyprogesterone (after 24 to 48 hours of life), androstenedione, testosterone, DHT, LH, FSH, AMH and inhibin B, cortisol, renin and ACTH, 11-deoxycortisol, DHEAS, and urinary steroid profile (GC-MS).
• Pelvic and abdominal ultrasound for uterus and gonads, genitogram or cystoscopy and vaginoscopy for urogenital sinus anatomy, MRI where unclear, and exploratory laparoscopy with gonadal biopsy when needed.
• Hormonal stimulation: hCG stimulation test (hCG 1500 units IM daily for 3 days, with testosterone and DHT rise indicating functional Leydig cells and conversion), ACTH stimulation (cosyntropin 250 micrograms, with 17-hydroxyprogesterone).
• Genetic testing: next-generation sequencing panels (NR5A1, AR, SRD5A2, HSD17B3, SRY, MAMLD1, WT1, CYP21A2, others), chromosomal microarray.

Adolescents with primary amenorrhoea

• Karyotype, gonadotropins, testosterone, AMH, pelvic ultrasound or MRI, and androgen receptor testing.

Klinefelter syndrome

• Karyotype (47,XXY), required to confirm. Chromosomal microarray or non-invasive prenatal testing may detect it prenatally.
• Hormones: low or low-normal testosterone, elevated LH and FSH, low inhibin B, and raised oestradiol. Testosterone may be normal in early puberty.
• Semen analysis (azoospermia, rarely severely oligozoospermic), testicular ultrasound, DEXA, lipids, glucose, HbA1c, haemoglobin, thyroid tests, and vitamin D.
• Neurodevelopmental, speech, and psychosocial evaluation.

General principles for DSD

• Management by an experienced multidisciplinary team (paediatric endocrinology, urology or surgery, gynaecology, genetics, psychology, social work, neonatology, ethics). Open honest communication with parents, provide peer support, avoid hasty sex assignment, and aim for informed decisions with consideration of the individual's future gender identity.
• Sex of rearing depends on diagnosis, genital appearance, surgical options, potential for sexual function and fertility, hormone exposure and family wishes. Gender identity may differ later.
• Timing of surgery is debated. Procedures that are not urgent (feminising genitoplasty, gonadectomy of non-malignant tissue) are deferred until the individual can participate, except where there is risk to health (urinary obstruction, high tumour risk).

Congenital adrenal hyperplasia (21-hydroxylase deficiency)

• Hydrocortisone 10 to 15 mg/m2/day in 3 divided doses in children (adults prednisolone 3 to 5 mg or dexamethasone 0.25 to 0.5 mg), fludrocortisone 0.05 to 0.2 mg daily, and salt supplementation (1 to 2 g sodium chloride daily) in infants. Stress dosing: hydrocortisone 50 to 100 mg/m2 IV/IM in illness or surgery. Monitor 17-hydroxyprogesterone, androstenedione, growth and bone age. Details are in the article on congenital adrenal hyperplasia.

Androgen insensitivity syndrome

• Complete: raised as female. Gonadectomy after puberty (orchidectomy at age 14 to 16, or maintained under surveillance given low tumour risk of about 2% before puberty), then oestradiol replacement (transdermal 50 to 100 micrograms twice weekly or oral 1 to 2 mg daily). Vaginal dilation for a shortened vagina. Bone density monitoring and psychological support.
• Partial: depends on phenotype and sex of rearing. High-dose testosterone may improve virilisation in male assignment.

5-alpha reductase 2 and 17-beta-HSD3 deficiency

• Management dictated by sex of rearing and gender identity. Testosterone enanthate or DHT gel (for 5-alpha reductase deficiency) in male rearing, and gonadectomy before virilising puberty in female rearing.

Gonadal dysgenesis

• Y-chromosome containing: early gonadectomy because of tumour risk (gonadoblastoma 15 to 35%). Swyer syndrome: oestrogen puberty induction, then cyclical progestogen, and egg donation for pregnancy.
• Mixed gonadal dysgenesis: gonadectomy of the dysgenetic gonad, growth hormone, and sex assignment individualised.

Müllerian agenesis (MRKH): vaginal dilators as first-line (80 to 90% success), surgical neovagina (Vecchietti, Davydov, McIndoe, sigmoid), and uterus transplantation or gestational surrogacy for fertility.

Persistent Müllerian duct syndrome: orchidopexy and preservation of testes, with removal of Müllerian structures only where safe.

Surgical considerations

• Hypospadias repair, orchidopexy, feminising genitoplasty (clitoral and vaginal reconstruction) when indicated, with consent and timing individualised. Gonadal tumour risk dictates removal of dysgenetic gonads: high risk in intra-abdominal gonads with Y material, low risk in complete androgen insensitivity before puberty.

Klinefelter syndrome

• Testosterone therapy: start when testosterone is low or at the onset of puberty with falling levels (around 12 years), as puberty induction in adolescents (enanthate 25 mg IM monthly, increasing every 6 months to adult dose over 2 to 3 years). Adult regimens: testosterone undecanoate 1000 mg IM every 10 to 14 weeks, gel 1.62% 40.5 mg daily, or enanthate 100 to 200 mg every 2 weeks, with target testosterone mid-normal range (400 to 700 ng/dL), haematocrit (stop above 54%), PSA and bone density monitoring. Improves energy, mood, muscle and bone mass, libido and body composition.
• Fertility: microdissection testicular sperm extraction (micro-TESE) yields sperm in 40 to 50% (younger men and higher baseline testosterone do better), with ICSI. Testosterone therapy should be stopped before sperm retrieval, or use hCG and FSH or aromatase inhibitor (anastrozole 1 mg daily) or clomiphene preceding retrieval. Fertility preservation in adolescents is experimental. Pregnancy outcomes with ICSI are generally good, and offer preimplantation or prenatal testing (the risk of sex chromosome aneuploidy in offspring is small).
• Gynaecomastia: tamoxifen 10 to 20 mg daily or anastrozole in early painful disease, surgical mastectomy for persistent. Annual breast examination, and awareness of breast cancer.
• Bone and metabolic health: calcium 1000 to 1200 mg and vitamin D 800 to 2000 IU daily, exercise, DEXA every 2 to 3 years, bisphosphonate for osteoporosis, and screening for diabetes, dyslipidaemia, hypertension, and obesity with lifestyle and drug therapy.
• Neurodevelopment and psychosocial: early speech therapy, educational support, occupational therapy, ADHD and anxiety treatment (methylphenidate 10 to 60 mg daily), counselling, and peer support (KS associations).
• Surveillance: venous thromboembolism risk assessment, thyroid and autoimmune screening, cardiovascular risk, and mediastinal tumour awareness.

Genetic counselling and follow-up

• Genetic counselling for recurrence risks (autosomal recessive, X-linked, or de novo), prenatal diagnosis where applicable. Lifelong multidisciplinary follow-up, with transition to adult services and attention to sexual function, fertility, bone health, mental health and cancer surveillance.