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Summary Table

Feature	Details
Risk Factors	Family history of constitutional delay, chronic illness (Crohn disease, celiac disease, cystic fibrosis, sickle cell disease), excessive exercise, malnutrition, CNS tumors/radiation, Turner syndrome (46,XX with 45,X), Klinefelter syndrome (47,XXY), anorexia nervosa
Etiology	Constitutional delay of growth and puberty (most common overall), functional hypogonadotropic hypogonadism (chronic disease, stress), permanent hypogonadotropic hypogonadism (Kallmann syndrome, pituitary lesions), hypergonadotropic hypogonadism (gonadal failure)
Patient Presentation	Girls: no breast development by age 13, or no menarche by age 15. Boys: no testicular enlargement (volume <4 mL) by age 14. Short stature relative to peers, psychosocial distress
Classic Physical Exam	Tanner stage I at an age beyond the expected onset. Boys: prepubertal testes (<4 mL). Girls: absent thelarche. Kallmann syndrome: anosmia. Turner syndrome: short stature, webbed neck, shield chest, widely spaced nipples. Klinefelter syndrome: tall eunuchoid habitus, small firm testes, gynecomastia
Key Diagnostic Results	Bone age delayed (constitutional delay) vs. normal/near-normal (hypogonadism). LH/FSH low in hypogonadotropic causes, elevated in hypergonadotropic causes. Karyotype abnormal in Turner (45,X) and Klinefelter (47,XXY). MRI brain for suspected CNS pathology
Management	Constitutional delay: reassurance, watchful waiting, or short course of low-dose sex steroids. Hypogonadotropic: treat underlying cause or hormone replacement. Hypergonadotropic: sex steroid replacement therapy. Kallmann: pulsatile GnRH or gonadotropin therapy if fertility desired
Keywords	"Anosmia + delayed puberty" (Kallmann), "short girl with webbed neck" (Turner), "tall boy with small testes" (Klinefelter), "bone age less than chronological age," "family history of late bloomer," "no breast buds by 13," "no testicular enlargement by 14"

1. Pathophysiology

Puberty is initiated by the reactivation of the hypothalamic-pituitary-gonadal (HPG) axis. Pulsatile secretion of GnRH from the hypothalamus stimulates the anterior pituitary to release LH and FSH, which in turn act on the gonads to produce sex steroids (testosterone in males, estradiol in females) and drive the development of secondary sexual characteristics. Any disruption along this axis can result in delayed puberty.

The most common cause overall is constitutional delay of growth and puberty (CDGP), a benign and self-limited condition. These patients have a tempo of maturation that is slower than average but eventually progress through puberty on their own. The hallmark is a bone age that is significantly delayed compared to chronological age, meaning the skeletal maturation clock is simply running behind. There is almost always a family history of a parent who was also a "late bloomer." Because the growth plates remain open longer, these children often reach a normal adult height, which is an important reassurance point.

In contrast, hypogonadotropic hypogonadism involves a deficiency at the level of the hypothalamus or pituitary. GnRH, LH, and FSH are all low, and therefore the gonads are never adequately stimulated. The classic inherited form is Kallmann syndrome, caused by failed migration of GnRH neurons from the olfactory placode during embryogenesis. This shared developmental origin explains the pathognomonic association of anosmia or hyposmia with delayed puberty. Functional causes of hypogonadotropic hypogonadism include chronic systemic illness, excessive exercise, stress, and malnutrition, all of which suppress pulsatile GnRH secretion through increased hypothalamic sensitivity to negative feedback and elevated cortisol.

Hypergonadotropic hypogonadism results from primary gonadal failure. Because the gonads cannot produce adequate sex steroids, there is loss of negative feedback to the pituitary, and LH and FSH rise markedly. The two highest-yield causes are chromosomal: Turner syndrome (45,X) in girls, where streak gonads fail to produce estrogen, and Klinefelter syndrome (47,XXY) in boys, where seminiferous tubule dysgenesis leads to small, firm testes with impaired testosterone production and infertility.

2. Classification and Clinical Manifestation

Category	Mechanism	LH/FSH	Key Clinical Features
Constitutional Delay of Growth and Puberty	Slow tempo of HPG axis maturation	Low (prepubertal)	Short stature, delayed bone age, family history of late puberty, eventual spontaneous progression
Functional Hypogonadotropic Hypogonadism	Reversible suppression of GnRH (chronic disease, malnutrition, excessive exercise)	Low	Features of underlying illness (e.g., weight loss, chronic diarrhea, fatigue). Puberty resumes once the underlying cause is corrected
Permanent Hypogonadotropic Hypogonadism	Structural or genetic defect at hypothalamus/pituitary	Low	Kallmann syndrome: anosmia, may have midline defects (cleft lip/palate), renal agenesis. Pituitary tumors (e.g., craniopharyngioma): headache, visual field defects, other pituitary hormone deficiencies
Hypergonadotropic Hypogonadism (Primary Gonadal Failure)	Gonadal destruction or dysgenesis	High	Turner syndrome: short stature, webbed neck, shield chest, bicuspid aortic valve, coarctation of aorta, streak gonads. Klinefelter syndrome: tall stature, eunuchoid proportions (arm span > height), small firm testes, gynecomastia, learning difficulties. Gonadal damage: post-chemotherapy, post-radiation, autoimmune oophoritis, bilateral orchitis (mumps)

A practical clinical point: the first sign of puberty in girls is thelarche (breast budding), corresponding to Tanner breast stage II, and the first sign in boys is testicular enlargement to 4 mL or greater. When these milestones are absent at the threshold ages (13 in girls, 14 in boys), a formal workup is indicated.

3. Diagnostic Workup

Test	Purpose	What It Tells You
Bone age (left hand and wrist X-ray)	Best initial test in most presentations	Delayed bone age favors constitutional delay. Bone age concordant with chronological age suggests true hypogonadism
Serum LH and FSH	Distinguish central from gonadal causes	Low/prepubertal: hypogonadotropic (central). Elevated: hypergonadotropic (gonadal failure)
Serum testosterone (boys) / estradiol (girls)	Confirm gonadal output	Low in both hypogonadotropic and hypergonadotropic states
Karyotype	Evaluate for chromosomal abnormalities	45,X (Turner), 47,XXY (Klinefelter)
GnRH stimulation test	Distinguish constitutional delay from permanent hypogonadotropic hypogonadism	Pubertal LH response suggests constitutional delay with imminent puberty. Flat response suggests permanent GnRH deficiency
Brain MRI with focus on sella and olfactory region	Rule out CNS lesion	Craniopharyngioma, pituitary adenoma, absent olfactory bulbs (Kallmann)
Additional labs	Screen for chronic disease	CBC, ESR, CRP, celiac panel (anti-tTG IgA), thyroid function, prolactin, IGF-1

Workup logic. The evaluation begins with a thorough history (growth trajectory, family pubertal timing, nutritional status, sense of smell, chronic illness symptoms) and physical exam (Tanner staging, testicular volume by orchidometer, stigmata of Turner or Klinefelter).

The best initial test is a bone age radiograph of the left hand and wrist. If bone age is significantly delayed compared to chronological age (typically by 2 or more years), constitutional delay is the leading diagnosis, particularly when there is a positive family history. This is the single most useful test for distinguishing a "late bloomer" from pathologic causes.

The next critical step is measuring basal LH and FSH. This separates the two main pathologic categories. If gonadotropins are elevated, the problem is at the gonad (hypergonadotropic hypogonadism), and a karyotype becomes essential to identify Turner or Klinefelter syndrome. If gonadotropins are low or inappropriately normal, the problem is central (hypogonadotropic hypogonadism). At this point, a brain MRI is indicated to exclude a structural lesion such as craniopharyngioma or pituitary pathology, and olfactory bulb assessment can confirm Kallmann syndrome.

The GnRH stimulation test is the most accurate test for differentiating constitutional delay from permanent hypogonadotropic hypogonadism when the clinical picture is unclear. Administration of exogenous GnRH with measurement of the LH response can reveal whether the pituitary is primed (suggesting imminent puberty, as in constitutional delay) or unresponsive (suggesting permanent deficiency). However, this test has imperfect sensitivity in practice and is often supplemented by serial clinical observation.

4. Management and Treatment

Condition	Treatment	Details
Constitutional Delay	Reassurance with or without short-course sex steroids	Boys: testosterone enanthate or cypionate 50-100 mg IM monthly for 3-6 months. Girls: low-dose ethinyl estradiol 5-10 mcg/day or transdermal estradiol patch for 3-6 months. Goal is to "jump-start" puberty, then observe for spontaneous progression
Kallmann Syndrome	Hormone replacement or gonadotropin therapy	For pubertal induction: testosterone (boys) or estradiol (girls) in gradually increasing doses. For fertility: pulsatile GnRH via pump, or combination hCG + FSH (menotropins) to stimulate spermatogenesis or ovulation
Turner Syndrome	Growth hormone + estrogen replacement	GH therapy started early to optimize height (0.05 mg/kg/day). Estrogen replacement initiated around age 11-12 (low-dose transdermal estradiol, gradually increased). Progesterone added after 2 years or at breakthrough bleeding to induce cycling. Lifelong hormone replacement needed
Klinefelter Syndrome	Testosterone replacement	Begin at pubertal age with gradually escalating doses. Lifelong testosterone replacement. For fertility: consider testicular sperm extraction + ICSI (limited success)
Functional Hypogonadotropic	Treat underlying cause	Nutritional rehabilitation, treat chronic disease, reduce exercise intensity. HPG axis recovers once the underlying stressor is corrected

Management logic. For constitutional delay, the first step is always reassurance and education about the self-limited nature of the condition. If the patient has significant psychosocial distress, a brief course of low-dose sex steroids can be offered to initiate secondary sexual characteristics without compromising final adult height. This is given for 3 to 6 months and then discontinued to see if endogenous puberty takes over.

For permanent hypogonadotropic hypogonadism, the approach depends on whether fertility is a current goal. For pubertal induction, gradually escalating sex steroid replacement is used: testosterone in boys (starting at 50 mg IM monthly, increasing every 6 months to full adult replacement doses of 200 mg every 2 weeks), and estradiol in girls (starting with low-dose transdermal patches, increasing over 2-3 years, with progesterone added later). If fertility is desired later in life, pulsatile GnRH therapy or gonadotropin injections (hCG + recombinant FSH) can stimulate the gonads directly.

For Turner syndrome, management is twofold: growth hormone to optimize final height (started as early as possible, often well before the expected age of puberty) and estrogen replacement to induce puberty, typically beginning around age 11-12 with very low doses to mimic normal physiologic progression and avoid premature epiphyseal fusion. These patients require lifelong estrogen-progesterone replacement and screening for associated cardiovascular anomalies (bicuspid aortic valve, coarctation) and renal malformations.

For Klinefelter syndrome, testosterone replacement is the mainstay of treatment, begun at the expected age of puberty and continued lifelong. It improves virilization, bone density, muscle mass, and psychosocial well-being. Fertility is severely compromised, though advances in testicular sperm extraction have provided limited options.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Constitutional delay vs. Kallmann syndrome	Both present with delayed puberty and low LH/FSH	Constitutional delay has delayed bone age and positive family history of late puberty. Kallmann has anosmia, bone age closer to chronological age, and no spontaneous pubertal progression
Constitutional delay vs. Growth hormone deficiency	Both cause short stature and delayed bone age	GH deficiency has low IGF-1 and abnormal GH stimulation test, and puberty may actually begin at a normal time but height gain is poor. Constitutional delay has normal GH axis
Turner syndrome vs. Noonan syndrome	Both feature short stature, webbed neck, and cardiac defects	Turner is 46,XX phenotype with 45,X karyotype, affects only females, and has streak gonads with elevated FSH. Noonan has a normal karyotype, affects both sexes, has pulmonary stenosis (not coarctation), and gonads are often functionally normal
Klinefelter syndrome vs. Simple obesity in adolescent males	Both can present with gynecomastia	Klinefelter has small, firm testes (<6 mL in adulthood), tall eunuchoid habitus, elevated LH/FSH, and karyotype shows 47,XXY. Obese males have normal-sized testes and normal gonadotropins
Functional hypothalamic amenorrhea vs. Permanent hypogonadotropic hypogonadism	Both have low LH/FSH and absent menses	Functional amenorrhea has identifiable stressor (low weight, excessive exercise, psychological stress) and reverses with correction of the underlying cause. Permanent forms do not recover
Prolactinoma vs. Other causes of hypogonadotropic hypogonadism	Elevated prolactin suppresses GnRH, causing low LH/FSH and delayed/arrested puberty	Prolactinoma has elevated serum prolactin, and may present with galactorrhea and headache. Treatment with cabergoline restores the HPG axis

6. Traps and High-Yield Pearls

The single most common trap on this topic is confusing constitutional delay with pathologic hypogonadism. Exam vignettes describing a short adolescent boy with a family history of a father who "grew late" and a bone age 2-3 years behind chronological age are almost always pointing toward constitutional delay. The correct answer is reassurance (with or without short-course testosterone), not a brain MRI or karyotype. Conversely, if the vignette adds anosmia, the answer shifts immediately to Kallmann syndrome, which requires hormone replacement rather than watchful waiting.

A second classic trap is Turner syndrome presenting without the classic phenotype. Not all Turner patients have obvious webbed neck and short stature at the time of the vignette. Some present subtly as a teenage girl with primary amenorrhea and mildly short stature. The test-writer expects you to check a karyotype when you see a girl with elevated FSH and absent pubertal development, even without dramatic dysmorphic features.

Another frequently tested concept is knowing the gonadotropin pattern. The entire diagnostic framework hinges on whether LH and FSH are high or low. High gonadotropins mean the pituitary is working hard because the gonads are failing (hypergonadotropic, think Turner or Klinefelter). Low gonadotropins mean the problem is upstream at the hypothalamus or pituitary (hypogonadotropic, think Kallmann, constitutional delay, or functional suppression). This single lab result is the branching point for the entire differential, and test-writers rely on it repeatedly.

Finally, remember that the first sign of puberty differs by sex: breast budding (thelarche) in girls and testicular enlargement in boys. Pubic hair (adrenarche) is driven by adrenal androgens and is not a reliable marker of HPG axis activation. A boy with pubic hair but prepubertal testes still has delayed puberty, and a vignette written this way is specifically testing whether you know the difference between adrenarche and gonadarche.

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