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A 7-year-old boy is brought to the physician for severe facial acne that has developed
over the past few months. His mother tried treating it with topical benzoyl peroxide and a
salicylic acid face wash with no improvement. She has also noticed a significant
increase in her son's growth, and he is now much taller than his fraternal twin brother.
The child is otherwise healthy with no chronic medical conditions, and he takes no
medications. His height is at the 98th percentile and weight is at the 85th percentile for
age and sex. Skin examination shows severe cystic acne involving the face and
shoulders, coarse pubic and axillary hair, and a normal testicular volume of 2 mL
bilaterally. Neurologic examination is normal. Bone age is 2 standard deviations higher
than chronological age. Luteinizing hormon.e levels are low at baseline and do not
increase after stimulation with a gonadotropin-releasing hormone agonist. Which of the
following is the most likely diagnosis in this patient?

0 A Exogenous testosterone abuse

0 B. Idiopathic precocious puberty
o C. Klinefelter syndrome
0 D. Leydig cell tumor
o E. Nonclassic congenital adrenal hyperplasia
0 F. Severe hypothyroidism

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A 7-year-old boy is brought to the physician for severe facial acne that has developed
over the past few months. His mother tried treating it with topical penzoyl peroxide and a
salicylic acid face wash with no improvement. She has also noticed a significant
increase in her son's growth, and he is now much taller than his fraternal twin brother.
The child is otherwise healthy with no chronic medical conditions, and he takes no
medications. His height is at the 98th percentile and weight is at the 85th percentile for
age and sex. Skin examination shows severe cystic acne involving the face and
shoulders, coarse pubic and axillary hair, and a normal testicular volume of 2 mL
bilaterally. Neurologic examination is normal. Bone age is 2 standard deviations higher
than chronological age. Luteinizing hormone levels are low at paseline and do not
increase after stimulation with a gonadotropin-releasing hormone agonist. Which of the
following is the most likely diagnosis in this patient?

A. Exogenous testosterone abuse [7%]

B. Idiopathic precocious puberty [24%]
C. Klinefelter syndrome [5%]
D. Leydig cell tumor [41%]
E. Nonclassic congenital adrenal hyperplasia [24%)
F. Severe hypothyroidism [0%)

Proceed to Next Item

Explanation: User

Central versus peripheral precocious puberty

Secondary sexual development
Girls age <8 years
or
Boys age <9 years

Bone age

Advanced Normal
Item: ~?Mark <? C> 6f ~ ~ , ~
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Central versus peripheral precocious puberty

Secondary sexual development
Girls age <8 years
or
Boys age <9 years

Bone age

Advanced Normal

Basai LH
Isolated breast Isolated
development pubic hair

Low LH High LH
+ +
Premature Premature
t thelarche adrenarche
GnRH
stimulation test
I
t t
Low LH High LH
+
Gonadotropin- Gonadotropin-dependent
independent (peripheral) c... (central)
precocious puberty precocious puberty
@USMLEWorld, U C

Precocious puberty is categorized as gonadotropin-dependent (central) precocious

puberty, gonadotropin-independent (peripheral) precocious puberty, or incomplete
precocious puberty (Flow chart). Bone age should pe performed in all patients with early
development of secondary sexual characteristics to assess for advanced skeletal
maturation. Luteinizing hormone (LH) levels should be measured .before and after
gonadotropin-releasing hormone (GnRH) stimulation to determine whether the patient's
precocious development is peripheral or central. In gonadotropin-independent
precocious puberty, LH levels are low at baseline and do not increase after stimulation
with a GnRH agonist.
precocious development is peripheral or central. In gonadotropin-independent
precocious puberty, LH levels are low at baseline and do not increase after stimulation
with a GnRH agonist.
This child's severe facial acne, advanced pubic and axillary hair, and normal testicular
volume for age are consistent with gonadotropin-independent precocious puberty caused
by late-onset (nonclassic) congenital adrenal hyperplasia (CAH) secondary to
21-hydroxylase (CYP21A2) deficiency. This enzyme converts
17-hydroxyprogesterone to 11-deoxycortisol and is deficient in approximately 90% of
children with CAH. Classic CAH presents in the neonatal period with adrenal
insufficiency and/or ambiguous genitalia; late-onset CAH manifests in late childhood with
signs of androgen excess. Clinical manifestations of late-onset CAH include
premature adrenarche/pubarche, severe cystic acne resistant to treatment,
accelerated linear growth, and advanced bone age, all of which are present in this
patient. Patients with classic CAH have salt-wasting; those with late-onset CAH have
normal electrolytes.
(Choice A) Although exogenous testosterone abuse does cause virilization (including
hirsutism and acne) secondary to gonadotropin-independent precocious puberty, it is
generally seen in adolescent male athletes rather than in younger children.

(Choice B) Idiopathic precocious puberty is characterized by premature activation of the

hypothalamic-pituitary-gonadal axis. It accounts for 80% of gonadotropin-dependent
precocious puberty and occurs almost exclusively in girls. Basal levels of LH are usually
elevated and will increase with GnRH stimulation, making this diagnosis unlikely.
(Choice C) Klinefelter syndrome (47,XXY) is the most common cause of primary
hypogonadism. Characteristic features include small testes, gynecomastia, a small
phallus, hypospadias, and cryptorchidism. It does not present with precocious puberty.
(Choice 0) Leydig cell tumors can cause gonadotropin-independent precocious puberty
but typically present with unilateral testicular enlargement or a testicular mass.

(Choice F) In rare cases, severe untreated primary hypothyroidism can present with
gonadotropin-dependent precocious puberty. Boys typically present with premature
testicular enlargement and short stature rather than accelerated linear growth. This
patient also lacks other hypothyroidism symptoms such as constipation, cold intolerance,
and fatigue, making this diagnosis unlikely.
Educational objective:
In gonadotropin-independent (peripheral) precocious puberty, luteinizing hormone levels
are low at baseline and do not increase after stimulation with a gonadotropin-releasing
hormone agonist. Advanced bone age, coarse axillary and pubic hair, and severe cystic
acne are seen in late-onset (nonclassic) congenital adrenal hyperplasia caused by
Item: ~?Mark <? C> S ~ ~ , ~
Q. ld : 4239 Prev1ous Next Lab Values Notes Calculator Reverse Color Text Zoom

17-hydroxyprogesterone to 11 -deoxycortisol and is deficient in approximately 90% of

children with CAH. Classic CAH presents in the neonatal period with adrenal
insufficiency and/or ambiguous genitalia; late-onset CAH manifests in late childhood with
signs of androgen excess. Clinical manifestations of late-onset CAH include
premature adrenarche/pubarche, severe cystic acne resistant to treatment,
accelerated linear growth, and advanced bone age, all of which are present in this
patient. Patients with classic CAH have salt-wasting; those with late-onset CAH have
normal electrolytes.
(Choice A) Although exogenous testosterone abuse does cause virilization (including
hirsutism and acne) secondary to gonadotropin-independent precocious puberty, it is
generally seen in adolescent male athletes rather than in younger children.

(Choice B) Idiopathic precocious puberty is characterized by premature activation of the

hypothalamic-pituitary-gonadal axis. It accounts for 80% of gonadotropin-dependent
precocious puberty and occurs almost exclusively in girls. Basal levels of LH are usually
elevated and will increase with GnRH stimulation, making this diagnosis unlikely.
(Choice C) Klinefelter syndrome (47,XXY) is the most common cause of primary
hypogonadism. Characteristic features include small testes, gynecomastia, a small
phallus, hypospadias, and cryptorchidism. It does not present with precocious puberty.
(Choice 0) Leydig cell tumors can cause gonadotropin-independent precocious puberty
but typically present with unilateral testicular enlargement or a testicular mass.
(Choice F) In rare cases, severe untreated primary hypothyroidism can present with
gonadotropin-dependent precocious puberty. Boys typically present with premature
testicular enlargement and short stature rather than accelerated linear growth. This
patient also lacks other hypothyroidism symptoms such as constipation, cold intolerance,
and fatigue, making this diagnosis unlikely.

Educational objective:
In gonadotropin-independent (peripheral) precocious puberty, luteinizing hormone levels
are low at baseline and do not increase after stimulation with a gonadotropin-releasing
hormone agonist. Advanced bone age, coarse axillary and pubic hair, and severe cystic
acne are seen in late-onset (nonclassic) congenital adrenal hyperplasia caused by
21-hydroxylase deficiency.

References:
1. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
2. Extensive clinical experience: nonclassical 21-hydroxylase deficiency.

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