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- What are the mechanisms implicated in the development of precocious puberty
in children with primary hypothyroidism?
Numerous mechanisms have been postulated for the development of precocious
puberty in children with primary hypothyroidism. Loss of negative feedback of
thyroxine at the level of hypothalamus results in increased levels of thyrotropin-
releasing hormone (TRH), which acts on GnRH receptor (“specificity-spillover”) at
pituitary, thereby leading to increase in gonadotropin secretion (Van Wyk–
Grumbach phenomenon) particularly FSH. Further, delayed clearance of gonado-
tropins also contributes to increased levels of FSH. Despite increase in gonadotropins,
LH response to GnRH is prepubertal. Increased serum TSH acts on FSH receptor
at gonads (“specificity-spillover”) and possibly augmented FSH sensitivity due to
FSH receptor polymorphisms result in increased sex steroid production. - A 3-year-old girl presented with breast development Tanner stage 2 and vaginal
bleed. On examination, she had a café-au-lait macule. What is the likely
diagnosis?
Inappropriate progression of secondary sexual characteristics (menarche at
breast Tanner stage 2) suggests a diagnosis of GIPP and the presence of café-
au- lait macule points to a diagnosis of McCune–Albright syndrome (MAS).
MAS is characterized by a triad of polyostotic/monostotic fibrous dysplasia,
café-au-lait macule, and endocrinopathies, precocious puberty being the most
common endocrinopathy. Precocious puberty in MAS is a result of develop-
ment of follicular cyst in response to constitutive activation of Gsα-subunit of
FSH receptor, and café-au-lait macule is due to constitutive activation of
melanocyte- stimulating hormone (MSH) receptor. In patients with GIPP, there
is inappropriate progression of secondary sexual characteristics because of
rapid, inordinate, and excessive production of gonadal steroids resulting in
menarche prior to breast Tanner stage 4–5. This is because development of
breast requires exposure to relatively lower concentration of estradiol for a
prolonged duration, while development of uterus and endometrium requires
exposure to higher concentration of estradiol. - What are the unique features of precocious puberty in girls with MAS?
Precocious puberty associated with MAS is more common in girls and usually
presents in infancy. The most common presenting manifestation of precocious
puberty in girls with MAS is vaginal bleed, which may not always be accompa-
nied with breast development. Café-au-lait macule is usually present at diagno-
sis; however, skeletal fibrous dysplasia may not be present initially and often
evolve with time. Acyclical vaginal bleed and “waxing and waning” breast size
are other atypical manifestations of precocious puberty associated with MAS,
which occurs as a result of intermittent formation and involution of ovarian fol-
licular cyst, despite constitutive activation of FSH receptor. Further, these6 Precocious Puberty