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MBBS IV - Junior Clerkship WCS > JC112 (Paediatrics) - Premature Puberty: Puberty & Related Disorders > Flashcards

JC112 (Paediatrics) - Premature Puberty: Puberty & Related Disorders Flashcards

1
Q

Hormonal changes that start onset of puberty

A

Kisspeptins from hypothalamus bind to GPR54 (GPCR) on the hypothalamic neurons to secrete GnRH
Activation of hypothalamic-pituitary-gonadal axis:
- frequency and amplitude of hypothalamic GnRH pulses increases at onset of puberty
- gonadotrophs in anterior pituitary secrete pulses of gonadotrophin (LH, FSH)
- Gonads stimulated

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2
Q

Describe the gonadal development during puberty

A

Under LH and FSH pulses:
1. Ovaries: follicular development, produce oestrogen for breast development, enlargement of uterus

  1. Testes: stimulate Sertoli cells, Leydig cells produce testosterone&raquo_space; penile and scrotal development
  2. direct effect on growth plate, and indirect action by stimulation of growth hormone
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3
Q

Factors that modulate the onset of puberty

A
  1. Genetic factors
  2. Peripheral signs: intrauterine and postnatal growth, BMI and fat mass, insulin sensitivity, gonadal steroid levels
  3. Environmental signals: light, stress, environmental endocrine disruptors
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4
Q

Female puberty

  • Age of puberty onset
  • Signs of puberty onset
  • Timing of secondary sexual characteristics
A

Age of onset: 11 years old (same for both sex)

Signs:

  • Breast development
  • Public and axillary hair (simultaneous with breast growth)
  • Menarche

Timing:

  • 10.1 years: Breast budding
  • 11.2 years: Pubic hair growth
  • 12.2 years: Growth spurt (9 months after tanner stage 2 breast development)
  • 12.7 years: Menarche (2 years after breast budding)
  • 14 years: Mature breasts
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5
Q

Male puberty

  • Age of puberty onset
  • Signs of puberty onset
  • Timing of secondary sexual characteristics
A

Age of onset - 11 years old (same for both sex)

Signs of puberty onset

  • Increase testicular volume to 4mL first
  • Growth of penis and genitalia simultaneously with pubic hair
  • Breast enlargement

Timing:
11-15 years: histological spermatogenesis
13.5 years: ejaculation occurs, peak growth spurt, corresponding to testicular volume of 10-12 ml
17 years (bone age): sperm with adult morphology, motility and concentration

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6
Q

Gynaecomastia in puberty

  • Cause
  • Progression of breast tissue in puberty
A

Cause: High oestrogen production by aromatization of testosterone before testosterone achieves concentrations that can oppose the oestrogen

Progression:

  • Breast tissue often regresses within 2 years
  • Gynaecomastia remains permanent in obese boys, or conditions e.g. Klinefelter syndrome, Partial androgen resistance
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7
Q

Definition of precocious puberty

A

Onset of puberty at a younger age than expected for the normal population (i.e. >2 SDs earlier than population mean)

If sexual development in:
 Girls younger than 8 years
 Boys younger than 9 years

Adjusted age cut-off for ethnicity:
<7 years in white girls
<6 years in black girls

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8
Q

Major causes of precocious puberty

A

Isolated premature sexual characteristic

  • Primary hypothyroidism
  • Precocious pseudopuberty

Central precocious puberty

  • Idiopathic
  • CNS lesions: most commonly Benign Hypothalamic Hamartoma
  • Suprasellar tumors
  • Other CNS lesions…etc

Peripheral precocious puberty

  • Autonomous hyperproduction of estrogen/ androgens (e.g. Testicular or ovarian tumors)
  • Exogenous hyperestrogenism/ androgens
  • Congenital adrenal hyperplasia, Non-classical Adrenal hyperplasia, Androgen-producing tumors
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9
Q

Explain how primary hypothyroidism causes precocious puberty

A

Primary hypothyroidism&raquo_space; Increase TSH acts as weak agonist on FSH receptors&raquo_space; abnormal pattern of gonadotropin secretion:

 In girls: ovarian stimulation  isolated breast development
 In boys: testicular enlargement without other secondary sexual characteristics
 No pubertal progression in majority of cases
 Delayed bone age with poor growth velocity

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10
Q

Effect of central precocious puberty on growth

A

accelerated bone maturation causes early fusion of bone plates
compromises final adult height

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11
Q

Central precocious puberty

  • Effect on puberty development
  • Common causes
A

Effect on puberty development:
- Activation of HPG axis at an earlier age, causing isosexual pubertal development (e.g. breast budding in girls, testicular enlargement in boys)

Idiopathic in girls (>80%)

CNS lesions in boys (>80%):

  • benign hypothalamic hamartoma (Most common)
  • Suprasellar tumors
  • Previous meningoencephalitis
  • Major head trauma
  • Neurofibromatosis
  • Hyperprolactinemia
  • Activating mutation of GPR54, the GPCR mediating effects of kisspeptin
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12
Q

Precocious pseudopuberty

  • Definition
  • Hormonal disturbances
A

Definition: Gonadal/ adrenal sex steroid secretion not resulting from activation of HPG axis, i.e.
 Pituitary independent or Peripheral production

Hormonal disturbance: Loss of normal feedback&raquo_space; very high sex steroid concentrations despite low gonadotropins
Sex steroid disturbance:
 Isolated high androgen
 Isolated high oestrogen
 Combined androgen and oestrogen production

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13
Q

Causes of androgen overproduction in precocious pseudopuberty

A

Girls:
 Ovarian arrhenoblastomas
 Ovarian hyperthecosis

Boys:  
 Leydig cell tumors
 hCG-secreting tumors (e.g. hepatoblastomas, germ cell tumors
 McCune-Albright syndrome
 Familial testotoxicosis
Both sex: 
 Nonclassical (late- onset) adrenal hyperplasia
 Androgen- secreting adrenal tumors
 Generalized glucocorticoid resistance
 Cushing syndrome 
 Exogenous anabolic steroid abuse
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14
Q

Causes of estrogen overproduction in precocious pseudopuberty

A 
Girls: 
 Ovarian cysts
 Ovarian granulosa cell tumors
 Sertoli-Leydig cell tumors (isolated or as part of Peutz- Jeghers syndrome)
 McCune- Albright syndrome

Boys:
 Adrenal tumors
 Sertoli cell tumors (usually part of Peutz- Jeghers syndrome)

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15
Q

Name 2 syndromes associated with precocious pseudopuberty

A

McCune-Albright syndrome (MAS)

Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)

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16
Q

McCune-Albright syndrome

  • Predominant gender
  • Pathogenesis
A

multisystem disorder, predominantly female

Pathogenesis:
sporadic somatic mutation (missense) in the gene encoding the α-subunit of the G- protein that stimulates cAMP production:
- Mutation occurs early in embryogenesis
- Failure of phosphorylation of GTP to GDP&raquo_space; constitutive activation of adenylyl cyclase in multiple affected tissues: skin, bone, gonads

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17
Q

McCune-Albright syndrome

  • Signs of sexual precocity in female and male
A

signs of sexual precocity

Female:
- Autonomously functioning luteinized follicular cysts of the ovaries&raquo_space; estrogen production
- Pre-pubertal LH secretion with absent LH response to GnRH
- Precocious thelarche
Ix: USG in girls – multiple follicular cysts with an occasional large solitary cyst

Male:
- asymmetric enlargement of the testes

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18
Q

McCune-Albright syndrome

Classical triad of symptoms and Diagnostic criteria

A

Diagnosis – >2 features present in classic triad:

  1. Irregularly-edged hyperpigmented macules/ café au lait spots
    Characteristic features:
     Jagged “coast of Maine” borders
     Location respects midline of body (does not cross)
  2. Polyostotic fibrous dysplasia (>1 bone is replaced by fibrous tissue&raquo_space; weak bones, uneven growth, deformity)
  3. Multiple autonomous endocrinopathies:
    - gonadotropin-independent sexual precocity (most common)
    - Others: thyroid, adrenals, pituitary, parathyroids
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19
Q

Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)

  • Inheritance pattern
  • Pathogenesis
A

Inheritance: autosomal dominant inheritance, but only phenotypic in boys

Pathogenesis:
constitutively activating mutations of LH receptor
» premature Leydig and germinal cell maturation
» gonadotropin-independent precocious puberty

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20
Q

Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)

  • Age of presentation
  • Clinical presentation
A

gonadotropin-independent precocious puberty:

  • present at 2-5 years
  • Accelerated growth
  • Early secondary sexual characteristics: Virilization and Mild enlargement of testesto early-/ mid-pubertal range
  • Reduced adult height
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21
Q

Familial testotoxicosis/ familial male-limited precocious puberty (FMPP)

Hormonal disturbances
Investigations for confirmation of Dx
Treatment

A

Testosterone levels:
 Very high concentrations
 Source of secretion localized to testes

Gonadotropin levels
 In childhood: unstimulated/ prepubertal concentrations with minimal response to GnRH stimulation
 In puberty: lack of the usual pattern of LH pulsatility
 In adulthood: normal pattern of LH secretion and response to GnRH&raquo_space; fertile

Testicular biopsy: premature maturation of Leydig cell (hyperplasia), spermatogenic elements
Hormone profile: High Testosterone, Pre-pubertal/ low gonadotrophins, Low hCG

Tx: Androgen-receptor-blocking agents (ketoconazole); or Aromatase inhibitors

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22
Q

7 questions for formulating Ddx for abnormal puberty

A
  1. Onset of puberty
  2. Progression of clinical symptoms
  3. signs of exaggerated maturation: isosexual? Isolated sexual characteristics? Growth? Specific syndromal signs?
  4. Effects on predicted adult height/ Compromised final height?
  5. Psychological consequences
  6. Gonadotropin-dependent (precocious puberty) or independent cause (precocious pseudopuberty)
  7. Central precocious puberty: idiopathic or CNS lesion
23
Q

Outline history taking questions for abnormal puberty

A

Presentation:
- Isosexual development? Adrenarche/ Pubarche/ Thelarche/ Testicular enlargement?
- Growth and final adult height potential

Birth history – SGA (small for gestational age** major risk factor), birth complications

Past medical history:

  • past X-rays,
  • brain trauma,
  • neonatal meningoencephalitis
  • Brain tumors (e.g. hypothalamic, suprasellar, prolactinoma…)

Family history:

  • History of precocious puberty
  • Check mid-parental height

Pubertal milestones (precise timing and sequence)

Impact on psychological health/ wellbeing

24
Q

Effect of SGA on growth and development

A

SGA (small for gestational age)

more prone to precocious pubarche,
earlier onset of pubertal development and menarche
faster progression of puberty

25
Q

Outline P/E for abnormal puberty and development

A
  1. Neurologic system (includes neurocutaneous markers, optic fundi, visual field)&raquo_space; Central precocious puberty
  2. Endocrine system, thyroid examination (Primary hypothyroidism, Hyperprolactinemia, Adrenal hyperplasia/ tumor…)
  3. Tanner staging pubertal development – breast development, Testicle enlargement. Secondary sexual characteristics, signs of hyperandrogenism (virillization, oily skin, acne…)
  4. Scoliosis/ body asymmetry > imbalance in growth
  5. Growth chart*

6.

26
Q

Growth chart patterns that suggest underlying pathologies

A

 A rapid tempo of progression
 Advanced development
 Rapid linear growth
 Advanced skeletal maturation

27
Q

First-line investigations for abnormal puberty and development

A
  1. Hormonal profile: LH, FSH, oestradiol/testosterone, TFT, prolactin, β-hCG
  2. LHRH Test (Luteinizing Hormone Releasing Hormone)
  3. X-ray for bone age (bone maturation)
  4. MRI brain and pituitary gland with contrast - exclude CNS lesion
  5. Investigations for peripheral causes;
    - USG pelvis (girls) and adrenals
    - Measure 17OHP, DHEAS and testosterone (screen for non-classical congenital adrenal hyperplasia)
    - ACTH stimulation test
    - 24 hour urine free cortisol (Cushing’s syndrome)
  6. Investigation for unilateral testicular enlargement: Imaging for androgen-producing tumour within the larger testis
  7. Investigation for bilateral testicular enlargement: Confirm CPP or FMPP
28
Q

Ddx and confirmation tests for early pubarche only

early onset of pubic and axillary hair, acne

A

1) rapid growth and significantly advanced bone age&raquo_space; Confirm CAH, Non-classical AH, Adrenal tumor, Exogenous androgens

  • High Testosterone, High 17-OH- progesterone, High DHEAS
  • Adrenal and ovarian ultrasound

2) normal growth rate and mildly advanced bone age (5-7 years)&raquo_space; Idiopathic precocious puberty
- Prepubertal testosterone, Normal 17-OH-Progesterone, Pubertal level DHEAS

29
Q

Ddx and confirmation tests for early thelarche (breast development) only

A

Normal growth rate and non-advanced bone age (birth- 3 years)
» Idiopathic precocious thelarche

Rapid growth and significantly advanced BA
- McCune-Albright syndrome or exogenous estrogen&raquo_space; Prepubertal / Low LH and FSH level + Pubertal/ high estradiol level
- Central precocious puberty&raquo_space; Pubertal LH + FSH + Estradiol , Confirm with head MRI

30
Q

Ddx and confirmation test for concurrent thelarche and pubarche

A

Central precocious puberty&raquo_space; Pubertal LH and FSH and estradiol level, confirm with brain MRI

Peripheral precocious puberty: Adrenal or ovarian tumor producing estrogen and androgen
- Pre-pubertal LH and FSH level + Pubertal Estradiol and testosterone
- Confirm with Adrenal and ovarian ultrasound

31
Q

Interpret the following presentation:

Pubarche only with normal growth rate
Pre-pubertal testosterone level
Normal 17-OH-Progesterone
Pubertal DHEAS level

Most likely cause of precocious puberty

A

Idiopathic precocious adrenarche

32
Q

Interpret the following presentation:

  • Pubarche only
  • Rapid growth
  • High testosterone, 17-OH- Progesterone and DHEAS

Most likely cause of precocious puberty

A

CAH, NCAH, adrenal tumor, exogenous androgen

33
Q

Interpret the following profile:

  • Thelarche only
  • Normal growth

Most likely cause of precocious puberty

A

idiopathic precocious thelarche

34
Q

Interpret the following profile:

  • Thelarche only with rapid growth
  • Prepubertal LH and FSH level
  • Pubertal estradiol level

Most likely cause of precocious puberty

A

McCune-Albright syndrome

Exogenous source of estrogen

35
Q

Interpret following profile:

  • Thelarche only
  • Rapid growth
  • Pubertal LH and FSH
  • Pubertal Estradiol level

Most likely cause of precocious puberty

A

Central precocious puberty

36
Q

Interpret the following profile:

  • Thelarche and pubarche present concurrently
  • LH, FSH and Estradiol levels all at pubertal level

Most likely cause of precocious puberty

A

Central precocious puberty

37
Q

Interpret following profile

Thelarche and pubarche
LH and FSH at prepubertal level
Estradiol and testosterone at pubertal level

Most likely cause of precocious puberty

A

Adrenal or ovarian tumor producing both estrogen and androgens

38
Q

Ddx and confirmation test for Symmetrical, prepubertal-sized testicles in boys with precocious puberty

A

Extra-testicular, gonadotropin- independent etiologies:

CAH, NCAH or adrenal tumor:
- Prepubertal LH and FSH
- High testosterone, 17-OHP, DHEAS
- Confirm with adrenal ultrasound

Exogenous testosterone
- Prepubertal LH and FSH
- Isolated high testosterone

39
Q

Ddx and confirmation test for asymmetrical testicular enlargement in boys

A

Functioning testicular tumor

  • LH and FSH at prepubertal level
  • Testosterone at pubertal level
  • Confirm with testicular US
40
Q

Ddx and confirmation test for symmetrical, pubertal-sized testes in boys

A

Gonadotropin mediated:
1) Central precocious puberty

  • Pubertal LH and FSH
  • Suppressed/ undetectable hCG
  • High testosterone
  • Confirm with Head MRI

2) hCG-producing germ cell tumor

  • LH and FSH at prepubertal level
  • High hCG
  • High testosterone

3) Familial testotoxicosis or McCune-Albright syndrome: autonomous testicle function

  • LH and FSH at prepubertal level
  • Undetectable hCG
  • High testosterone
41
Q

Interpret the following profile for ddx of precocious puberty

Symmetrical pubertal-sized testes

  • LH and FSH at prepubertal level
  • High hCG
  • High testosterone
A

hCG-producing germ cell tumor

  • LH and FSH at prepubertal level
  • High hCG
  • High testosterone
42
Q

Interpret the following profile for ddx of precocious puberty

Symmetrical pubertal-sized testes

  • LH and FSH at prepubertal level
  • Undetectable hCG
  • High testosterone
A

Familial testotoxicosis or McCune-Albright syndrome: autonomous testicle function

43
Q

Interpret the following profile for ddx of precocious puberty

Symmetrical pubertal-sized testes

  • Pubertal LH and FSH
  • Suppressed/ undetectable hCG
  • High testosterone
A

Central precocious puberty

44
Q

Interpret the following profile for ddx of precocious puberty

asymmetrical testicular enlargement

  • LH and FSH at prepubertal level
  • Testosterone at pubertal level
A

Functioning testicular tumor

45
Q

Interpret the following profile for ddx of precocious puberty
Symmetrical, prepubertal-sized testicles

  • Prepubertal LH and FSH
  • High testosterone
  • 17-OH-progesterone
A

CAH, NCAH or adrenal tumor

46
Q

Interpret the following profile for ddx of precocious puberty
Symmetrical, prepubertal-sized testicles

  • Prepubertal LH and FSH
  • Isolated high testosterone
A

Exogenous testosterone

47
Q

central precocious puberty

  • Indication for treatment
  • Treatment option
  • Route and timing of administration
  • Benefit
A

Reasons for treatment:

  1. Preservation of adult height potential
  2. Psychological difficulties with early puberty and menarche

Option:
GnRH analogues (leuprolide acetate) - Provides constant serum levels of GnRH activity and overrides pulsatility of endogenous GnRH
IM injection once every 4 weeks
Benefit in preserving/ increasing adult height

48
Q

Peripheral precocious puberty

  • Indication for treatment
  • Treatment option
  • Benefit
A

Indication: depends on cause

Ovarian/ Adrenal Tumours: surgical removal ± chemotherapy and/or radiation therapy
Ovarian cysts: drainage under USG guidance
Exogenous oestrogens/ androgens: uncover and eliminate
 Non-classical CAH: exogenous glucocorticoid

Additional GnRH agonist if central puberty starts concomitantly

49
Q

Premature thelarche

  • Definition
  • S/S
  • Progression
  • Ix
A
  • isolated breast development in girls between 2-7 years

S/S:

  • 50% bilateral
  • Volume: Tanner stage B2, B3
  • Tender breasts
  • No discharge (c.f. genital crisis of newborn with milk production)

Progression:

  • Spontaneous remission over 18 months
  • Persistent
  • Aggravate breast development with increased bone maturation

Ix for persistent thelarche: LHRH test – predominant FSH response

50
Q

Premature adrenarche/ pubarche:

  • Definition
  • Gender predominance
  • Effect on growth
  • S/S
A

appearance of pubic hair before 8 years old

More common in girls

Effect:
Slight increase Growth velocity and bone age maturation
Significant Maturation of adrenal function

S/S of hyperandrogenism:
- acne, abnormal perspiration, clitoral hypertrophy, oily skin

51
Q

Premature adrenarche/ pubarche:

Complication
Ix for ddx

A

Complication:

  • PCOS (20% risk)
  • Exaggerated adrenarche: presents as subtle androgen excess and insulin resistance (central adiposity, acanthosis nigricans)

Ix to Exclude congenital adrenal hyperplasia:

  • Androgen work-up: high testosterone, high 17-OH-P, high DHEA
  • synacthen test: Low cortisol
52
Q

exaggerated adrenarche

  • Effect on growth
  • S/S
  • Complication
  • Ix
A

Growth:
Slightly advanced onset of true puberty
Height potential not compromised

S/S:
Subtle androgen excess: significant bone age advancement but not clitoromegaly
Insulin resistance (central adiposity, acanthosis nigricans)

Complications
- PCOS

Ix:
Adrenal steroid levels - mid to late pubertal range/ high
Testosterone: under adult female range

53
Q

Isolated premature menarche

  • Definition
  • Effect on growth
  • S/S
A

menstruation without other signs of puberty in a young girl before 9 years of age

Effect:

  • Menstruation may recur cyclically
  • Transient ovarian activity&raquo_space; Rise in oestrogenization&raquo_space; accelerated bone maturation +/- breast development

S/S:
 Foreign body
 Local masses
 McCune- Albright syndrome

54
Q

Isolated premature menarche

Ix
Tx

A

Ix:
Inconsistent response to LHRH test
Functional ovarian cysts on UG pelvis

Tx:
 Observe with close longitudinal follow-up
 Stop puberty (rarely undertaken)

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