Disorders of Sexual Differentiation, Growth & Puberty

Forfar & Arneil 7th Edition · 46,XX & 46,XY DSD · Gonadal dysgenesis · Growth assessment · Bone age · Pubertal staging (Tanner) · Variations of puberty · Adult height prediction
📌 Key principles: Normal sexual differentiation requires SRY gene (testis determination), testosterone synthesis/action (male genitalia), and anti-Müllerian hormone (regression of female ducts). Growth assessment: accurate height velocity, bone age predicts remaining growth. Puberty: Tanner staging, normal ranges 8-13y (girls) 9-14y (boys).

📖 Disorders of Sexual Differentiation, Growth & Puberty

🧬 Sexual differentiation – key steps
Chromosomal sex (46,XX/46,XY) → gonadal sex (SRY gene on Y → testis) → phenotypic sex (testosterone → male ducts, external genitalia; AMH → regression of Müllerian ducts).
⚧ 46,XX DSD (virilized female)
Most common: 21-hydroxylase deficiency (CAH). Other: 11β-hydroxylase deficiency, maternal androgens (tumour, exogenous), aromatase deficiency.
🩸 46,XY DSD (undervirilized male)
Androgen synthesis defects (17β-HSD, 5α-reductase), androgen insensitivity (complete/partial), gonadal dysgenesis (Swyer), Leydig cell hypoplasia.
📏 Growth assessment
Accurate height/weight on centile charts. Height velocity (cm/yr) essential. Bone age (left wrist X-ray) predicts remaining growth and adult height (Bayley-Pinneau, TW3).
⏳ Puberty – Tanner staging
Girls: breast development (B1-B5), pubic hair (PH1-PH5). Menarche ~2y after B2. Boys: testicular volume (>4ml start), genital staging (G1-G5), pubic hair. Adrenarche (pubic hair) may precede gonadarche.
📊 Key clinical pearls: Tall child with delayed bone age? Consider constitutional delay. Short child with advanced bone age? Consider obesity, precocious puberty, hyperthyroidism, GH excess. Pubertal variations: premature thelarche (isolated breast), premature adrenarche (pubic hair only), both benign.

🔍 Clinical approach to DSD, growth disorders & pubertal variations

1
Newborn with ambiguous genitalia – immediate priorities – Exclude salt-wasting CAH (electrolytes, 17-OHP). Karyotype (rapid FISH). Pelvic ultrasound (uterus/presence of Müllerian structures). Do NOT assign gender without complete evaluation.
2
46,XX DSD evaluation – Virilized female. Confirm karyotype. Elevated 17-OHP → 21-hydroxylase deficiency. Normal 17-OHP → 11β-hydroxylase (elevated 11-deoxycortisol), maternal androgens, aromatase deficiency.
3
46,XY DSD evaluation – Undervirilized male. Karyotype 46,XY. hCG stimulation test (testosterone response). Anti-Müllerian hormone (AMH) level (testicular presence). Testosterone/DHT ratio (5α-reductase deficiency). Androgen receptor gene (AR) for androgen insensitivity.
4
Growth assessment – short stature – Accurate height, plot on centile. Calculate height velocity. Bone age X-ray. Screen for chronic disease, thyroid, IGF-1. GH stimulation tests if low IGF-1 or growth velocity poor.
5
Puberty – normal timing & variations – Girls: breast development 8-13y, menarche ~12.5y. Boys: testicular volume >4ml 9-14y. Premature thelarche (isolated breast, no growth acceleration, normal bone age). Premature adrenarche (pubic hair only, normal growth).
6
Delayed puberty evaluation – Tanner staging, bone age, LH/FSH, testosterone/oestradiol. Constitutional delay (CDGP) vs hypogonadotropic hypogonadism (low LH/FSH) vs hypergonadotropic (high LH/FSH).
📌 Clinical pearl: In a newborn with ambiguous genitalia, do not discharge before electrolytes and 17-OHP results. Salt-wasting CAH can present with collapse on day 5-14. Karyotype is essential but not urgent for lifesaving treatment.

📋 Stepwise management of DSD, growth & pubertal disorders

1
DSD – gender assignment (multidisciplinary team) – Decision based on diagnosis, potential for fertility, genital appearance, gonadal cancer risk, parental views. Avoid gonadectomy in 46,XY DSD with uterus unless risk; typical female rearing for complete androgen insensitivity, male for 5α-reductase deficiency (if diagnosed early).
2
CAH (46,XX virilized) – Glucocorticoid (hydrocortisone) + mineralocorticoid (fludrocortisone) if salt-wasting. Monitor 17-OHP, electrolytes, renin, growth. Genitoplasty (clitoral reduction, vaginoplasty) after 6-12 months.
3
Androgen insensitivity syndrome (complete) – Female gender rearing. Remove gonads after puberty (due to malignancy risk ~5-10% after age 20). Oestrogen replacement. No uterus, so infertility.
4
Growth hormone therapy indications – GH deficiency, Turner syndrome, Prader-Willi, SGA without catch-up, CKD, SHOX deficiency. Dose 25-50 mcg/kg/day subcutaneous. Monitor height velocity, IGF-1, bone age.
5
Delayed puberty – constitutional delay – Reassurance. If psychosocial distress: low-dose testosterone (boys 50-100 mg IM monthly x 4-6 months) or oestrogen (girls 0.3-0.6 mcg/kg/day). Monitor bone age.
6
Precocious puberty – central (GnRH-dependent) – GnRH agonist (leuprolide) monthly IM. Halts pubertal progression, improves adult height. Peripheral precocious puberty: treat underlying cause (CAH with glucocorticoids, McCune-Albright with aromatase inhibitors).
7
Adult height prediction – Bone age (Greulich-Pyle or TW3). Bayley-Pinneau method: use bone age and current height to predict final height. Target height from mid-parental height ± 8.5 cm (girls) or ±10 cm (boys).
⚠️ Key points in puberty assessment: Testicular volume >4ml indicates onset of gonadarche (boys). Breast development (Tanner B2) is first sign in girls. Pubic hair can appear from adrenarche independent of gonadal steroids.

🧠 Reflex prompts: DSD, growth & puberty

👶 A newborn with ambiguous genitalia (clitoromegaly, labioscrotal fusion), palpable gonads bilaterally, no uterus on ultrasound. Karyotype 46,XY. Most likely?
46,XY DSD – differential: complete androgen insensitivity (female external, testes, no uterus), 5α-reductase deficiency, gonadal dysgenesis.
🧬 A 46,XX virilized newborn with salt-wasting. Diagnosis and urgent test?
21-hydroxylase deficiency CAH. Urgent: electrolytes, 17-OHP. Treatment: hydrocortisone + fludrocortisone.
📏 A 7-year-old boy height <3rd centile, bone age 4 years, normal IGF-1. What is the most likely diagnosis?
Constitutional delay of growth (CDGP) or GH deficiency. GH stimulation test needed. Family history of delayed growth supports CDGP.
👧 A 6-year-old girl with breast development (Tanner B2), no pubic hair, bone age normal. Most likely?
Premature thelarche (benign isolated breast development). No growth acceleration, normal bone age, regression over time. Differentiate from precocious puberty.
🩺 A 14-year-old boy with no testicular enlargement (volume 2ml), pubic hair Tanner 2, bone age 12y, LH/FSH low. Most likely?
Constitutional delay of puberty (CDGP) vs hypogonadotropic hypogonadism. Family history, and response to GnRH stimulation (CDGP shows response, HH does not).
🧫 A 46,XY phenotypic female with primary amenorrhea, absent uterus, testes in inguinal canals. Karyotype confirms 46,XY. Diagnosis?
Complete androgen insensitivity syndrome (CAIS). Testosterone levels high (normal male). AR gene mutation. Gonadectomy after puberty due to malignancy risk.
📊 A 10-year-old tall boy with advanced bone age, rapid growth, but no pubertal signs. Next step?
Exclude growth hormone excess (IGF-1, GH suppression test) and hyperthyroidism (TSH, fT4). Familial tall stature likely if normal.
⏰ A 13-year-old girl with no breast development, but pubic hair Tanner 3. Bone age 11y. What is the most likely?
Premature adrenarche (pubic hair from adrenal androgens) with delayed breast development – could be constitutional delay. Check FSH, LH, oestradiol.
🦴 How is adult height predicted from a bone age X-ray?
Bayley-Pinneau method: uses bone age (Greulich-Pyle or TW3) and current height to read percentage of adult height achieved. Target height from mid-parental height.
⚧ A 46,XY newborn with microphallus, bifid scrotum, palpable testes, low DHT/testosterone ratio. Diagnosis?
5α-reductase deficiency. Autosomal recessive, impairs conversion of testosterone to DHT. May virilize at puberty (testosterone surge).