Human Development

Pubertal development: Tanner staging and abnormal patterns

Clinical Overview and When to Suspect Abnormal Puberty

— Girls: thelarche (breast budding) age 8–13; menarche typically 2–2.5 years after thelarche, average 12.5

— Boys: testicular enlargement (≥4 mL or ≥2.5 cm length) age 9–14; first sign of true puberty

— Pubarche (pubic hair) from adrenarche can occur independently and is not by itself proof of central puberty

— Stage 1: prepubertal

— Stage 2: first physical change (breast bud / testes ≥4 mL / sparse straight pubic hair)

— Stage 3: further breast mound / penile lengthening / coarser darker hair

— Stage 4: areolar mound / scrotal darkening / adult-type hair not on thighs

— Stage 5: adult contour

— Precocious puberty: secondary sexual characteristics before 8 in girls, 9 in boys

— Delayed puberty: absence of thelarche by 13 in girls or testicular volume <4 mL by 14 in boys; primary amenorrhea by 15 despite breast development; failure to complete puberty within 5 years of onset

— Contrasexual development: virilization in a girl, feminization (gynecomastia beyond mild pubertal) in a boy

— Discordant tempo: pubarche without thelarche, or thelarche that arrests

— Rapid Tanner progression (<6 months stage-to-stage)

— Bone age advanced >2 SD over chronologic age

— Growth velocity crossing percentiles up (precocious) or down (delayed/central pathology)

— CNS symptoms: headache, vision changes, polyuria → suspect intracranial lesion

— Café-au-lait macules, fibrous dysplasia → McCune-Albright

— Family history of constitutional delay vs. anosmia (Kallmann)

Board pearl: The first sign of true puberty is breast budding in girls and testicular enlargement ≥4 mL in boys — pubic hair alone reflects adrenarche and does not localize to the HPG axis.

Normal pubertal timing (US norms)

Tanner staging anchors

Define abnormal patterns

When to suspect pathology on Step 3

Presentation Patterns and Key History

— Normal girl sequence: thelarche → pubarche → growth spurt → menarche

— Normal boy sequence: testicular enlargement → pubarche → penile growth → growth spurt (peak height velocity at Tanner 3–4, later than girls)

— Key distinction: Girls have their growth spurt early (Tanner 2–3); boys have it late (Tanner 3–4). A short boy at Tanner 2 may still catch up.

— Age of onset, rate of progression, growth acceleration

— CNS red flags: headaches, vomiting, visual field cuts, seizures

— Exogenous exposure: testosterone gels (parent's), estrogen creams, lavender/tea tree oils, OCPs

— Skin findings: café-au-lait (>6, >15 mm, jagged "coast of Maine" → McCune-Albright)

— Abdominal pain or mass (ovarian/adrenal tumor)

— Family pattern of "late bloomers" (constitutional delay — most common cause)

— Anosmia/hyposmia (Kallmann)

— Chronic illness: IBD, celiac, CF, CKD, anorexia, intense athletic training

— Chemotherapy/radiation history

— Headache, galactorrhea (prolactinoma)

— Newborn issues: micropenis, cryptorchidism, midline defects (congenital hypogonadotropic hypogonadism)

— Primary amenorrhea: no menses by 15 with secondary sex characteristics, or by 13 without any

— Cyclic pelvic pain without menses → imperforate hymen / transverse vaginal septum / Müllerian anomaly

— Plot height, weight, BMI, and mid-parental height

— Calculate growth velocity (prepubertal nadir ~5 cm/yr)

Step 3 management: First office step for any concern about pubertal timing is to obtain a bone age X-ray of the left hand and wrist and plot growth velocity — these two data points triage nearly the entire differential.

Tempo and sequence matter more than a single finding

Precocious puberty history

Delayed puberty history

Menstrual history in girls

Growth chart review is mandatory

Physical Exam Findings and Tanner Documentation

— B1: prepubertal, no glandular tissue

— B2: breast bud, areolar widening; tissue palpable beneath areola

— B3: breast and areola enlarge together, single contour

— B4: areola and papilla form secondary mound above breast

— B5: adult contour, areola recedes to breast plane

— Pitfall: lipomastia in obese girls mimics B2 — palpate for true glandular tissue

— G1: testes <4 mL (or <2.5 cm length)

— G2: testes 4–8 mL, scrotal thinning/reddening — heralds puberty

— G3: testes 9–12 mL, penile lengthening

— G4: testes 15–20 mL, penile width and glans develop

— G5: testes >20 mL, adult genitalia

— Asymmetric testes: unilateral enlargement suggests Leydig cell tumor; bilateral small testes with virilization suggests adrenal source or CAH

— PH1 none; PH2 sparse straight along labia/base of penis; PH3 darker, curlier, spreading; PH4 adult-type, not on thighs; PH5 spread to medial thighs

— Height, weight, BMI, arm span (arm span > height by >5 cm suggests delayed epiphyseal closure → hypogonadism, Klinefelter, Marfan)

— Skin: acne, hirsutism (Ferriman-Gallwey), acanthosis nigricans, café-au-lait

— Thyroid, visual fields, fundoscopy, sense of smell

— Abdominal/pelvic exam for mass; external genital exam for clitoromegaly, virilization, ambiguity

— Tanner discordance: breast development without pubic hair in a girl → think androgen insensitivity (if also primary amenorrhea)

Board pearl: Testicular volume ≥4 mL is the earliest objective sign of central puberty in boys — if testes are prepubertal but virilization is present, the source is extra-gonadal (adrenal, exogenous, hCG-secreting tumor).

Breast staging (girls) — palpate, don't just look

Genital staging (boys) — use orchidometer

Pubic hair (both sexes)

Additional exam

Diagnostic Workup — Initial Labs and Bone Age

— Advanced bone age (>2 SD above chronologic): precocious puberty, CAH, exogenous androgens, hyperthyroidism

— Delayed bone age: constitutional delay, hypothyroidism, chronic illness, hypogonadism, GH deficiency

— Key distinction: In constitutional delay, bone age = height age < chronologic age (proportional delay). In hypothyroidism or GH deficiency, bone age is delayed but disproportionately so, and growth velocity is poor.

— LH, FSH (basal): elevated → primary gonadal failure (hypergonadotropic); low/normal in central process

— Estradiol (girls) or morning total testosterone (boys)

— TSH, free T4 (hypothyroidism causes both delay and Van Wyk-Grumbach precocious puberty)

— Prolactin if galactorrhea, delayed puberty, or amenorrhea

— Pubertal LH cutoff: basal LH ≥0.3 IU/L suggests central activation

— GnRH (leuprolide) stimulation test — gold standard

— Peak LH >5 IU/L → central (gonadotropin-dependent)

— Suppressed LH with elevated sex steroids → peripheral (gonadotropin-independent)

— Add 17-hydroxyprogesterone (non-classic CAH), DHEA-S (adrenal), β-hCG (germ cell tumor in boys with precocious puberty)

— Low LH/FSH with low sex steroids → hypogonadotropic (central or constitutional)

— High LH/FSH with low sex steroids → hypergonadotropic (primary gonadal failure → karyotype: Turner 45,X in girls, Klinefelter 47,XXY in boys)

— CBC, CMP, ESR, celiac serologies, IGF-1 for chronic disease screen

Step 3 management: A basal LH <0.3 IU/L in the setting of premature thelarche makes central precocious puberty unlikely — observation with growth/bone-age monitoring is often sufficient, sparing GnRH stimulation testing.

Bone age (left hand/wrist X-ray) — the cornerstone study

First-tier hormonal labs

Precocious puberty workup

Delayed puberty workup

Advanced and Confirmatory Studies

— Mandatory in: all boys with central precocious puberty (>50% have intracranial pathology — hamartoma, glioma, germinoma)

— Girls with central precocious puberty if age <6, neurologic symptoms, or rapid progression (younger = higher yield)

— Delayed puberty with low gonadotropins to exclude tumor, infiltrative disease, empty sella

— Hypothalamic hamartoma = classic cause of central precocious puberty with gelastic seizures

— Uterine length >3.5 cm, endometrial stripe, and ovarian volume >2–3 mL with follicles suggest estrogen exposure

— Identify ovarian cyst/tumor in peripheral precocious puberty

— Absent uterus with normal breasts + primary amenorrhea → Müllerian agenesis (MRKH) or complete androgen insensitivity (differentiate by karyotype and testosterone)

— All girls with primary hypergonadotropic hypogonadism (Turner)

— All boys with small firm testes, tall stature, gynecomastia, learning issues (Klinefelter)

— Suspected disorders of sex development

— ACTH stimulation test for non-classic 21-hydroxylase deficiency (17-OHP >10 ng/mL post-stim)

— hCG stimulation test in boys to confirm functional Leydig cells when basal testosterone low

— Olfactory testing / smell identification + MRI olfactory bulbs for Kallmann

— DEXA for bone density in chronic hypogonadism

— β-hCG, AFP for germ cell tumors

— DHEA-S, androstenedione, urinary 17-ketosteroids for adrenal tumors

— Inhibin B, AMH for granulosa cell tumors

Board pearl: A boy with central precocious puberty gets a brain MRI — period. The pretest probability of CNS lesion is high enough that imaging is standard of care, unlike in young girls where idiopathic CPP dominates.

Brain MRI with pituitary protocol

Pelvic/abdominal ultrasound (girls)

Karyotype

Specialized endocrine testing

Tumor markers when indicated

Risk Stratification and Management Logic

— Step 1: Is it true puberty (progressive, with growth acceleration and bone age advancement) vs. benign variant (premature thelarche, premature adrenarche, premature menarche)?

— Step 2: Central (GnRH-dependent) vs. peripheral (GnRH-independent)?

— Step 3: If central — idiopathic vs. CNS lesion (MRI)

— Step 4: If peripheral — gonadal, adrenal, exogenous, McCune-Albright, familial male-limited (testotoxicosis)

— Premature thelarche: isolated breast development in girls <2–3 yrs, non-progressive, normal bone age, normal growth velocity

— Premature adrenarche: pubic/axillary hair, body odor, no breast/testicular development, mildly advanced bone age; associated with later PCOS and metabolic syndrome

— Premature menarche: isolated vaginal bleeding without other puberty — rule out trauma, abuse, foreign body, vulvovaginitis, tumor

— Most common cause overall: constitutional delay of growth and puberty (CDGP) — diagnosis of exclusion, often familial, bone age delayed but proportional

— Functional hypogonadotropic hypogonadism: anorexia, athletic triad, chronic illness — treat underlying cause

— Permanent hypogonadotropic: Kallmann, CHARGE, Prader-Willi

— Permanent hypergonadotropic: Turner, Klinefelter, chemo/radiation, autoimmune oophoritis

— Preserve adult height (precocious)

— Achieve normal pubertal development, peak bone mass, fertility potential, psychosocial well-being

— Treat underlying disease

Step 3 management: In a 7-year-old girl with isolated breast development, normal growth velocity, and bone age within 1 year of chronologic age, the answer is reassurance and reevaluation in 3–6 months — not GnRH analog therapy.

Decision tree for precocious puberty

Benign variants — observe, don't treat

Delayed puberty triage

Treatment goals

Pharmacotherapy — GnRH Analogs and Hormone Replacement

— Leuprolide depot IM monthly or every 3 months; histrelin SC implant lasting 12 months; triptorelin depot

— Mechanism: continuous GnRH receptor stimulation → desensitization → suppressed LH/FSH

— Indications: progressive CPP with bone age advancement compromising adult height, or significant psychosocial distress

— Monitor: pubertal regression (breast/testicular size stable or regressing), bone age every 6–12 months, growth velocity, LH suppression (<4 IU/L post-stim or basal LH <1)

— Stop: around bone age 12–12.5 in girls, 13–13.5 in boys, or chronologic age ~11 to allow normal pubertal completion

— Side effects: injection site reaction, sterile abscess, headache, initial pubertal flare (first 1–2 weeks), rare reduced BMD (transient)

— McCune-Albright: letrozole (aromatase inhibitor) or tamoxifen in girls; spironolactone + letrozole or bicalutamide + anastrozole in boys

— Familial male-limited (testotoxicosis): bicalutamide (anti-androgen) + aromatase inhibitor

— CAH: hydrocortisone ± fludrocortisone

— Tumors: surgical excision

— Exogenous exposure: remove the source

— Boys with CDGP: low-dose testosterone enanthate 50–100 mg IM monthly × 3–6 months to "jump-start" puberty

— Permanent hypogonadism in boys: gradually escalate testosterone to adult replacement dose

— Girls with permanent hypogonadism: low-dose transdermal estradiol, gradually increased over 2–3 years, then add cyclic progestin after breakthrough bleeding or 2 years of estrogen → mimics natural puberty

— Fertility induction later requires pulsatile GnRH or gonadotropins (hCG + FSH)

Board pearl: GnRH agonists work in central precocious puberty only — they are useless in peripheral causes because the problem is downstream of the pituitary.

Central precocious puberty — GnRH agonists

Peripheral precocious puberty — target the source

Delayed puberty — sex steroid replacement

Procedures and Surgical Considerations

— Hypothalamic hamartoma: usually managed medically with GnRH agonist; surgery/stereotactic radiosurgery reserved for intractable gelastic seizures

— Pituitary adenoma (prolactinoma): dopamine agonist (cabergoline) first; transsphenoidal resection if medication fails or large with mass effect

— Ovarian cysts/tumors: granulosa cell tumor, Sertoli-Leydig, dysgerminoma — surgical excision

— Adrenal tumors: adrenalectomy for virilizing or feminizing tumors

— Testicular Leydig cell tumor: testis-sparing surgery when feasible

— Cryptorchidism: orchidopexy by 6–18 months to preserve fertility and reduce cancer risk

— Imperforate hymen: hymenotomy (cruciate incision) — outpatient procedure

— Transverse vaginal septum: surgical resection

— Vaginal agenesis (MRKH): progressive vaginal dilation first-line; vaginoplasty if dilation fails — performed in adolescence when patient is motivated

— Gonadectomy due to dysgerminoma/gonadoblastoma risk (up to 30% in Y-containing dysgenetic gonads)

— Timing: at diagnosis for Swyer/Y-mosaicism; after puberty completion in CAIS (lower risk, allows spontaneous feminization)

— Calcium 1300 mg/day and vitamin D 600–1000 IU/day during all hormone therapy

— Weight-bearing exercise; DEXA monitoring in prolonged hypogonadism

— Pre-chemotherapy/radiation: sperm banking (post-pubertal boys), oocyte cryopreservation (post-pubertal girls), experimental testicular/ovarian tissue cryopreservation for prepubertal children

CCS pearl: For a girl with primary amenorrhea, cyclic pelvic pain, and a bulging bluish vaginal membrane — order pelvic exam under sedation and consult gynecology for hymenotomy; imaging not required before the diagnostic exam.

Surgical indications in pubertal disorders

Genitourinary procedures

Streak gonads (Turner mosaic with Y material, Swyer syndrome, complete AIS)

Bone health interventions

Fertility preservation

Special Populations — Chronic Disease, Renal, Endocrine Comorbidities

— IBD, celiac disease, CF, sickle cell, JIA: functional hypogonadotropic hypogonadism via inflammation and undernutrition

— Treat underlying disease aggressively; puberty often resumes with disease control and nutritional rehabilitation

— Screen with tTG-IgA, CBC, ESR, albumin, CMP in any unexplained delay

— Delayed puberty common; uremia suppresses GnRH pulse generator and gonadal steroidogenesis

— Optimize dialysis adequacy, correct anemia (ESA), correct acidosis, ensure adequate caloric intake

— Growth hormone often indicated for CKD-related short stature pre-transplant

— Causes delayed puberty typically — but severe primary hypothyroidism causes Van Wyk-Grumbach syndrome: precocious puberty with breast development and multicystic ovaries from TSH cross-stimulating FSH receptors, paradoxically with delayed bone age (the only precocious puberty with delayed bone age)

— Treatment: levothyroxine reverses both

— Accelerates bone maturation, may cause menstrual irregularity, gynecomastia in boys

— Girls: earlier thelarche and menarche; mechanism involves aromatization and leptin signaling

— Boys: paradoxically may have delayed puberty; aromatization of androgens to estrogens, mild hypogonadotropic state

— Pseudogynecomastia (adipose) vs. true gynecomastia (glandular)

— Poor glycemic control delays puberty and menarche; tight control reverses

— Functional hypothalamic amenorrhea: low LH/FSH, low estradiol, low leptin

— Treatment: nutritional rehabilitation first, not OCPs (OCPs don't restore bone density)

Key distinction: Severe primary hypothyroidism is the one cause of precocious puberty with delayed bone age — every other cause advances bone age. Check TSH in any unusual precocious puberty presentation.

Chronic illness and puberty

Chronic kidney disease

Hypothyroidism

Hyperthyroidism

Obesity

Type 1 diabetes

Eating disorders / female athlete triad

Special Populations — Genetic Syndromes and Sex Chromosome Disorders

— Phenotype: short stature, webbed neck, shield chest, cubitus valgus, lymphedema, low hairline, bicuspid aortic valve, coarctation, horseshoe kidney

— Ovarian failure → primary amenorrhea or premature ovarian insufficiency

— Workup: karyotype, echocardiogram (aortic root), renal ultrasound, audiology, TFTs, celiac

— Step 3 management: Start growth hormone by age 4–6 to optimize adult height; start low-dose transdermal estradiol around age 11–12, escalate over 2–3 years, add progestin after 2 years or breakthrough bleeding

— Cardiac surveillance lifelong (aortic dissection risk, especially in pregnancy)

— Tall stature, eunuchoid body habitus (arm span > height), small firm testes (<6 mL despite virilization), gynecomastia, learning/behavioral issues, infertility

— Puberty often begins normally then arrests; testosterone falls in mid-puberty

— Treatment: testosterone replacement starting mid-adolescence; fertility may be possible with TESE-ICSI

— Increased risk: breast cancer, mediastinal germ cell tumors, metabolic syndrome, osteoporosis

— Congenital hypogonadotropic hypogonadism + anosmia/hyposmia (olfactory bulb agenesis)

— Anosmin-1 (KAL1) X-linked; FGFR1, PROK2 others

— Treatment: testosterone or estrogen induction; gonadotropins/pulsatile GnRH for fertility

Board pearl: A tall boy with small firm testes and gynecomastia = Klinefelter until proven otherwise → order karyotype.

Turner syndrome (45,X and variants)

Klinefelter syndrome (47,XXY)

Kallmann syndrome

Prader-Willi: hypotonia, hyperphagia, hypogonadotropic hypogonadism; treat with GH and sex steroid replacement

McCune-Albright: triad of polyostotic fibrous dysplasia + café-au-lait (coast of Maine) + endocrine hyperfunction (precocious puberty, hyperthyroidism, GH excess, Cushing) from GNAS mutation

Congenital adrenal hyperplasia (21-OH deficiency): virilization, premature pubarche, advanced bone age; non-classic form presents in adolescence

Complications and Adverse Outcomes

— Short adult stature from premature epiphyseal fusion (paradoxically tall as children, short as adults)

— Psychosocial: anxiety, depression, body image issues, age-inappropriate sexual behavior, increased risk of sexual abuse

— Early menarche → modestly increased lifetime risk of breast cancer and endometrial cancer (estrogen exposure)

— Metabolic syndrome, PCOS associations (especially with premature adrenarche)

— Low peak bone mass → osteoporosis, fracture risk

— Psychosocial: depression, social withdrawal, bullying

— Infertility if cause is permanent and untreated

— Eunuchoid proportions (delayed epiphyseal closure → long extremities)

— Initial pubertal flare (first 1–2 weeks) — counsel families

— Sterile abscess at injection site

— Transient decreased BMD (recovers post-treatment)

— Slight weight gain

— Rare: pseudotumor cerebri, anaphylaxis

— Reproductive function returns within ~12–18 months of discontinuation

— Estrogen: VTE risk (lower with transdermal), endometrial hyperplasia if unopposed → mandatory progestin once breakthrough bleeding or after 2 years

— Testosterone: erythrocytosis, acne, mood changes, accelerated bone age if dose too high in CDGP

— McCune-Albright: pathologic fractures from fibrous dysplasia

— Turner: aortic dissection (lifetime), hearing loss, hypothyroidism, osteoporosis

— Klinefelter: metabolic syndrome, T2DM, breast cancer, VTE

— CAH: adrenal crisis with stress, salt-wasting (classic forms)

Step 3 management: Counsel families of children on GnRH agonists that the first injection causes transient pubertal flare (vaginal spotting, breast tenderness) — this is expected, not treatment failure.

Of untreated precocious puberty

Of untreated delayed puberty

Of GnRH agonist therapy

Of sex steroid replacement

Of underlying conditions

When to Escalate — Referral and Specialist Involvement

— Any confirmed precocious or delayed puberty (beyond benign variants)

— Tanner stage regression or arrest

— Discordant puberty (e.g., advanced pubarche with absent thelarche)

— Suspected CAH, McCune-Albright, central or peripheral precocious puberty

— Turner, Klinefelter, Kallmann, other genetic causes

— Need for GnRH stimulation testing, hormone replacement, GnRH agonist initiation

— Neurosurgery / neuro-oncology: CNS lesion on MRI (hamartoma, glioma, germinoma, craniopharyngioma)

— Gynecology: primary amenorrhea with anatomic abnormality, Müllerian agenesis, imperforate hymen

— Urology: cryptorchidism, micropenis, hypospadias, testicular mass

— Genetics: any suspected chromosomal or syndromic disorder

— Adolescent medicine / psychology: eating disorders, body image distress, gender concerns

— Oncology: suspected germ cell, granulosa, Sertoli-Leydig, or adrenal tumor

— Cardiology: Turner syndrome (annual echo, MRA every 5 years)

— Headache + vomiting + visual changes + precocious puberty → emergent neuroimaging

— Adrenal crisis features in suspected CAH (hypotension, hyponatremia, hyperkalemia) → IV hydrocortisone, fluids, ICU

— Acute virilization with abdominal mass → urgent imaging for adrenal/ovarian tumor

— Initial growth/bone age assessment

— Reassurance for benign variants

— Reproductive counseling and anticipatory guidance

— Coordinate longitudinal follow-up

CCS pearl: A child presenting with new precocious puberty + headaches + diabetes insipidus triad suggests a suprasellar germinoma or Langerhans cell histiocytosis — order brain MRI urgently and consult endocrinology and neuro-oncology the same day.

Pediatric endocrinology referral indicated for

Other consults

Urgent/emergent indicators

Primary care role

Key Differentials — Within Pubertal Disorders

— Both: breast development before age 8

— Thelarche: non-progressive, no growth acceleration, normal bone age, prepubertal LH, no other secondary sex characteristics — observe

— CPP: progressive, growth velocity ↑, bone age advanced, pubertal LH response to GnRH stim

— Both: pubic hair, body odor, mild acne before age 8 (girls) or 9 (boys)

— Adrenarche: mildly elevated DHEA-S, normal 17-OHP, mildly advanced bone age, no virilization

— Non-classic CAH: elevated 17-OHP (basal >200, post-ACTH >1000 ng/dL), clitoromegaly possible, more advanced bone age

— Central: pubertal LH (basal or post-GnRH stim), proportional progression, testes enlarged (boys)

— Peripheral: suppressed LH, elevated sex steroids, often prepubertal testes with virilization in boys

— Both: low LH/FSH, low sex steroids, delayed bone age

— CDGP: family history of late puberty, bone age = height age, eventually progresses spontaneously, often a brief "kick-start" course of low-dose testosterone is diagnostic and therapeutic

— Permanent (Kallmann, CHARGE): anosmia, midline defects, micropenis/cryptorchidism in infancy, fails to progress

— Tools: GnRH agonist stimulation, inhibin B (low in permanent), prior pubertal milestones

— Primary + no breasts + low FSH → constitutional, hypothalamic, Kallmann

— Primary + no breasts + high FSH → Turner, gonadal dysgenesis, premature ovarian insufficiency

— Primary + breasts + uterus absent → MRKH (46,XX) vs. CAIS (46,XY) — check karyotype and testosterone

Key distinction: CDGP improves with time and may respond to a short testosterone trial; Kallmann does not and is associated with anosmia plus mirror movements/synkinesia, renal agenesis, cleft palate.

Premature thelarche vs. central precocious puberty

Premature adrenarche vs. CAH (non-classic)

Central vs. peripheral precocious puberty

Constitutional delay vs. permanent hypogonadotropic hypogonadism

Primary vs. secondary amenorrhea workup branches

Differentials — Conditions That Mimic Pubertal Disorders

— Vulvovaginitis (most common)

— Foreign body (toilet paper, small object) — malodorous discharge

— Trauma / sexual abuse — mandatory consideration

— Urethral prolapse

— Lichen sclerosus

— Rhabdomyosarcoma (sarcoma botryoides) — grape-like vaginal mass

— Exogenous estrogen exposure

— Lipomastia (obesity)

— Neonatal breast tissue (maternal estrogen, regresses)

— Drug-induced (risperidone, metoclopramide → hyperprolactinemia)

— Breast cyst, fibroadenoma

— Pubertal gynecomastia (40–60% of pubertal boys, Tanner 2–4, resolves in 1–2 years) — reassure

— Klinefelter

— Drugs: spironolactone, ketoconazole, cimetidine, marijuana, anabolic steroids, antipsychotics

— Hyperthyroidism, cirrhosis, renal failure

— Testicular/adrenal tumors (Leydig, hCG-secreting)

— Aromatase excess syndrome

— Familial short stature: normal bone age = chronologic age, normal growth velocity, normal puberty timing

— GH deficiency: delayed bone age, low growth velocity, low IGF-1

— Hypothyroidism: delayed bone age, weight gain, low TSH/T4

— Cushing: obesity + short stature + striae + buffalo hump

— Non-classic CAH

— Androgen-secreting tumor (ovary, adrenal)

— PCOS (adolescent)

— Exogenous androgens (parent's testosterone gel)

— Cushing's

Board pearl: Prepubertal vaginal bleeding always requires examination under anesthesia if outpatient exam is non-diagnostic — rule out foreign body, rhabdomyosarcoma (sarcoma botryoides), and abuse. Do not attribute to "early menarche" without workup.

Causes of isolated vaginal bleeding (not puberty)

Causes of isolated breast enlargement (not thelarche)

Causes of gynecomastia in boys

Causes of short stature mimicking delayed puberty

Causes of virilization in girls

Long-Term Management and Transition

— GnRH agonist until appropriate stopping age (bone age 12–12.5 girls, 13–13.5 boys, or chronologic age ~11)

— Resume natural puberty after discontinuation; menses typically return within 12–18 months in girls

— Adult height usually within target range if treated early enough

— Monitor adult metabolic, reproductive, psychological outcomes

— Lifelong sex steroid replacement

— Girls: cyclic estrogen + progestin, often transitioned to combined OCP for convenience after full development; transdermal estradiol preferred for VTE risk in Turner

— Boys: testosterone (IM enanthate/cypionate every 1–2 weeks, transdermal gel/patch, or long-acting undecanoate)

— Fertility planning: gonadotropins or pulsatile GnRH at appropriate age

— Bone health: DEXA every 2 years, calcium/vitamin D, weight-bearing exercise

— Cardiovascular risk: lipid panel, BP, glucose annually (Turner, Klinefelter, untreated hypogonadism increase risk)

— Begin transition planning at age 14–16

— Identify adult endocrinologist by age 18–21

— Comprehensive transition summary: diagnosis, genetics, prior imaging, hormone history, fertility status, comorbidity screening schedule

— Self-management skills: medication adherence, injection technique, recognizing adrenal crisis (CAH)

— Discuss fertility openly and early — many adolescents with Turner, Klinefelter, CAH can achieve parenthood with assistance

— Discuss sexuality and contraception even in patients with reduced fertility

— Mental health screening at every visit

Step 3 management: Adolescents with chronic endocrine diagnoses need a structured transition-of-care document by age 18 — this is a recognized patient-safety vulnerability point and a frequent Step 3 systems-based theme.

Long-term plan in central precocious puberty

Long-term plan in hypogonadism (permanent)

Transition to adult care

Anticipatory guidance

Follow-Up, Monitoring, and Counseling Cadence

— Reassess every 3–6 months × 1–2 years

— Plot growth, repeat Tanner staging, repeat bone age yearly if any progression

— Discharge from specialty follow-up if stable; continue routine pediatric care

— Clinical visit every 3 months: Tanner, growth velocity, side effects, adherence

— Bone age every 6–12 months

— LH/estradiol or testosterone every 6 months to confirm suppression

— Stop therapy when bone age 12–12.5 (girls) or 13–13.5 (boys) — earlier if psychosocial goals met

— Reassess every 6 months: growth, Tanner, bone age annually

— If on testosterone "jump-start", reassess after 3–6 month course — spontaneous progression of testicular volume confirms intact axis

— Initial: every 3 months for dose titration and side effect monitoring

— Maintenance: every 6–12 months

— Labs: estradiol/testosterone troughs, lipids, CBC (testosterone → erythrocytosis), LFTs, BMD every 2 years

— Pre-adolescent: anticipatory guidance on what to expect, body autonomy, hygiene

— Early adolescent: menstrual education, contraception, STI prevention, mental health, body image

— Late adolescent: fertility, transition to adult care, autonomy in management

— Educate caregivers and (with consent) school nurses about chronic conditions

— Address bullying related to physical differences

— Refer to support groups (Turner Syndrome Society, AXYS for Klinefelter, MAGIC Foundation)

Board pearl: In a child on GnRH agonist therapy, lack of pubertal regression after 6 months suggests either non-adherence, inadequate dose, or peripheral cause missed at initial workup — re-evaluate.

Benign variants (premature thelarche, premature adrenarche)

Central precocious puberty on GnRH agonist

Delayed puberty / CDGP

Hormone replacement therapy

Counseling topics by age

Family and school

Ethical, Legal, and Patient Safety Considerations

— Most US states allow adolescents to consent independently for reproductive health, contraception, STI care, and mental health — exact age varies by state

— Discuss limits of confidentiality at first visit: safety concerns (suicidality, abuse, homicidality) require breaking confidentiality

— Document parental presence/absence; offer one-on-one time with adolescent ≥age 12

— Suspected child sexual abuse in a prepubertal child with vaginal bleeding, STI, genital trauma, or precocious development inconsistent with medical cause → mandatory CPS report regardless of certainty

— Reasonable suspicion threshold, not proof

— STI in a prepubertal child (gonorrhea, chlamydia, syphilis, HIV) → near-pathognomonic for abuse, mandatory report

— Assent from adolescent + consent from guardian for GnRH agonists, sex steroids

— Disclose fertility implications, BMD effects, irreversibility (in some treatments), unknown long-term data

— For gender-affirming care: follow current professional guidelines and state law (highly variable); ensure mental health assessment

— Avoid irreversible surgery in infancy without medical necessity

— Multidisciplinary team: endocrinology, urology, genetics, psychology, ethics

— Engage family in shared decision-making; preserve future autonomy

— High-risk handoff at age 18–21: medication errors, lost-to-follow-up, adrenal crisis in CAH patients who stop hydrocortisone

— Use structured transition tools (Got Transition framework)

— Confirm adult provider received records before discharging from pediatric care

— Discuss before gonadotoxic therapy — even if family declines, document the discussion (failure to discuss is a recognized malpractice risk)

— Address minor's assent for invasive fertility preservation procedures

Step 3 management: In a 5-year-old girl with isolated vaginal bleeding, a normal exam, no estrogen exposure, and no other puberty signs, examination under anesthesia is indicated to rule out foreign body, rhabdomyosarcoma, and abuse — and a mandatory abuse evaluation is part of the workup, not optional.

Confidentiality and adolescent autonomy

Mandatory reporting

Informed consent for hormone therapy

Disorders of sex development (DSD)

Transition-of-care safety

Fertility preservation in cancer

High-Yield Associations and Rapid-Fire Facts

— Café-au-lait "coast of Maine" + fibrous dysplasia + precocious puberty → McCune-Albright

— Café-au-lait "coast of California" + axillary freckling → NF1

— Anosmia + delayed puberty → Kallmann

— Tall boy + small firm testes + gynecomastia → Klinefelter (47,XXY)

— Short girl + webbed neck + amenorrhea + bicuspid AV → Turner (45,X)

— Precocious puberty + gelastic seizures → hypothalamic hamartoma

— Severe hypothyroid + precocious puberty + delayed bone age → Van Wyk-Grumbach

— Prepubertal boy + virilization + asymmetric testis → Leydig cell tumor

— Prepubertal boy + virilization + symmetric prepubertal testes + elevated 17-OHP → CAH

— Tanner 5 breasts + absent uterus + 46,XY + blind vagina → complete androgen insensitivity

— Tanner 5 breasts + absent uterus + 46,XX → MRKH (Müllerian agenesis)

— Primary amenorrhea + Tanner 1 + tall stature + delayed bone age → check for hypogonadism, FSH/LH, karyotype

— Any pubertal concern → bone age + growth chart + Tanner

— Precocious + bone age advanced → LH, FSH, sex steroids, GnRH stim

— Boy with CPP → brain MRI mandatory

— Delayed + high FSH → karyotype

— Delayed + low FSH → MRI brain + smell test

— Central precocious puberty → GnRH agonist (leuprolide/histrelin)

— McCune-Albright → letrozole (girls), bicalutamide + AI (boys)

— CAH → hydrocortisone ± fludrocortisone

— CDGP → reassurance ± short testosterone "kick-start"

— Turner → GH then estradiol

— Klinefelter → testosterone replacement at mid-adolescence

— Imperforate hymen → cruciate hymenotomy

Board pearl: Across pediatric endocrinology, bone age is the single most useful test — it differentiates etiologies that look identical clinically.

Top buzzwords → diagnosis

First steps in workup

Treatment one-liners

Board Question Stem Patterns

Step 3 management: The most common trap is treating peripheral precocious puberty with a GnRH agonist — always confirm central vs. peripheral with LH response to GnRH stimulation before starting leuprolide.

Stem 1: 6-year-old girl with breast development and pubic hair × 6 months; height at 95th %ile up from 50th; bone age 9 years; basal LH 1.8 IU/L → central precocious puberty; next step: brain MRI (younger girls warrant imaging) then GnRH agonist

Stem 2: 14-year-old boy, height 10th %ile, testes 2 mL, no pubic hair; father didn't shave until age 17; bone age 12 years → constitutional delay of growth and puberty; management: reassurance ± short course low-dose testosterone

Stem 3: 15-year-old girl with no breast development, no menses, short stature, webbed neck, wide-spaced nipples → Turner; order karyotype + echocardiogram + renal US; treat with GH then estradiol

Stem 4: 16-year-old boy, tall, eunuchoid proportions, small firm testes 4 mL, gynecomastia, learning difficulties → Klinefelter; karyotype, then testosterone replacement

Stem 5: 3-year-old girl with vaginal bleeding, no breast development, normal growth, normal bone age → NOT puberty; evaluate for foreign body, trauma, abuse, rhabdomyosarcoma; examination under anesthesia

Stem 6: 7-year-old boy with pubic hair, penile enlargement, prepubertal testes (2 mL), advanced bone age, elevated 17-OHP → non-classic CAH (peripheral precocious puberty); GnRH agonist will NOT work; treat with hydrocortisone

Stem 7: 5-year-old girl with breast and pubic hair development, café-au-lait macules with irregular borders, recurrent fractures → McCune-Albright; treat with letrozole, NOT GnRH agonist (peripheral cause)

Stem 8: 16-year-old girl, Tanner 5 breasts, no menses, no pubic hair, blind-ending vagina, palpable inguinal masses → complete androgen insensitivity (46,XY); karyotype, gonadectomy timing post-puberty

Stem 9: 7-year-old girl with breast development, weight gain, fatigue, constipation, short stature, delayed bone age → severe primary hypothyroidism with Van Wyk-Grumbach; check TSH; treat with levothyroxine

Stem 10: 17-year-old male athlete with delayed puberty and anosmia → Kallmann; MRI brain, gonadotropin or testosterone therapy

One-Line Recap

Normal puberty begins with breast budding in girls (8–13) and testicular enlargement ≥4 mL in boys (9–14); deviations require bone age, growth velocity, and LH/FSH-based localization to central, peripheral, or constitutional causes — and a brain MRI in every boy with central precocious puberty.

Board pearl: When in doubt, order a bone age and replot the growth chart — these two interventions resolve more pubertal-disorder vignettes than any single hormone level.

Tanner anchors: B2/G2 marks puberty onset; girls' growth spurt is early (Tanner 2–3), boys' is late (Tanner 3–4) — explains why short pubertal boys often catch up.

Workup algorithm: bone age + growth chart + basal LH first; advanced bone age with pubertal LH = central precocious puberty (GnRH agonist after MRI); advanced bone age with suppressed LH = peripheral (treat the source — CAH, McCune-Albright, tumor, exogenous); delayed bone age proportional to height age = constitutional delay (reassure ± kick-start).

Don't-miss diagnoses: Turner in any short girl with delayed puberty (karyotype + echo), Klinefelter in any tall boy with small firm testes and gynecomastia (karyotype), Kallmann when anosmia accompanies delayed puberty, McCune-Albright with café-au-lait + fibrous dysplasia + precocity, Van Wyk-Grumbach when precocious puberty has paradoxically delayed bone age (check TSH), and abuse/foreign body/rhabdomyosarcoma in any prepubertal vaginal bleeding without other puberty signs.

Treatment essentials: GnRH agonists for central CPP only; letrozole/bicalutamide for peripheral causes; hydrocortisone for CAH; transdermal estradiol then cyclic progestin for hypogonadal girls; staged testosterone for hypogonadal boys; transition planning by age 18 with structured handoff to adult endocrinology to prevent the safety gaps that Step 3 loves to test.