195children should remain under regular surveillance as they may develop other
endocrinopathies like hyperthyroidism and acrogigantism during follow-up.- A 5-year-old boy presented with aggressive behavior. On examination, he had
penile enlargement with bilateral testicular volume 6 ml. His father also had
history of precocious puberty. Serum LH was undetectable and GnRH stimu-
lated LH was 1.1 mIU/ml. What is the likely diagnosis?
Bilateral testicular enlargement, disproportionate penile growth in relation to
testicular enlargement, undetectable LH, and prepubertal LH response to GnRH
with a family history of precocious puberty suggest the diagnosis of familial
testotoxicosis. Although precocious puberty in testotoxicosis is gonadotropin-
independent, there is an increase in testicular volume due to gain-of- function
mutation of LH receptor. Testicular enlargement occurs as a result of increased
intratesticular testosterone which directly promotes growth of seminiferous
tubules. Patients with testotoxicosis can have spermatogenesis, which is rare in
other causes of GIPP. A close differential diagnosis for testotoxicosis is preco-
cious puberty associated with MAS; however, the absence of café-au- lait macule
and fibrous dysplasia with presence of family history of precocious puberty
favor a diagnosis of familial testotoxicosis in the index patient. Further, testicu-
lar enlargement is usually asymmetrical in MAS, while it is symmetrical in
testotoxicosis. - Why is precocious puberty in familial testotoxicosis only confined to boys?
Familial testotoxicosis is due to the gain-of-function mutation of LH receptor
and is inherited in an autosomal dominant pattern. Boys with familial testotoxi-
cosis present with increased growth velocity, penile enlargement with sym-
metrical and moderate increase in testicular volume, premature pubarche, and
accelerated skeletal maturation. On the contrary, girls harboring LH receptor
mutations do not manifest with precocious puberty. This is because LH- induced
(due to LH receptor activation) ovarian androgens are not aromatized to estro-
gen in the absence of FSH, as aromatase activity is FSH-dependent. In addition,
FSH is essential for induction of LH receptors on theca cells. This also explains
the lack of development of precocious puberty in girls with hCG- secreting
tumors and the development of precocious puberty in McCune–Albright syn-
drome with gain-of-function mutation of Gsα subunit involving both FSH and
LH receptor.- What is “mixed precocious puberty”?
Premature reactivation of HPG-axis in a patient with GIPP is termed as “mixed
precocious puberty” (GDPP superimposed on GIPP). It is commonly seen in
children with CAH, McCune–Albright syndrome, and testotoxicosis who have
delayed initiation of treatment, particularly in those with advanced bone age6 Precocious Puberty