17 36.2 Stepwise Analysis
The index patient presented with breast development (B 3 ) at 3 years of age, which is
below the lower normal reference age for the onset of puberty (8 years), thereby,
qualifying the criteria for the diagnosis of precocious puberty. The children with
precocious puberty require further evaluation to prevent height loss and adverse psy-
chosocial outcome. In addition, it also helps to exclude the presence of structural
disease as a cause of precocious puberty, though less common in girls. The prema-
ture breast development in the index child could be due to gonadotropin-dependent
precocious puberty (GDPP), gonadotropin-independent precocious puberty (GIPP),
or premature thelarche (normal variant). Majority of children with premature thelar-
che present before the age of 4 years, and the breast development is usually up to
stage B 3 ; however, it is nonprogressive and regresses spontaneously within 6 months
to 6 years after the diagnosis. Other signs of sexual maturation like pubarche, men-
arche, and enlargement of uterus are absent. Further, growth velocity is normal in
these children, and there is no advancement in bone age. Though the index patient
presented at the age of 3 years with breast development (B 3 ), presence of growth
spurt (height +2SDS), advancement in bone age (BA > CA,7 > 3 years), and enlarge-
ment of uterus (4.1 cm, prepubertal uterine length <3.5 cm) exclude the diagnosis of
premature thelarche. Early age of onset of puberty (<2 years), dissociation between
breast staging and menarche (<B 3 and menarche), waxing and waning size of breast,
presence of cutaneous markers (cafe-au-lait macule, adenoma sebaceum, shagreen
patch, neurofibroma), bony deformity, feature suggestive of hypothyroidism (goiter
and delayed tendon reflexes), and palpable abdominal mass suggest the diagnosis of
GIPP. However, the absence of these features neither excludes the diagnosis of GIPP
nor confirms the presence of GDPP. Therefore, to differentiate between GDPP and
GIPP, estimation of basal and stimulated LH along with gonadal steroids is required.
Basal serum LH value of ≥0.3 mIU/ml or stimulated LH >8 mIU/ml (by chemilumi-
nescence assay) after triptorelin is diagnostic of GDPP. In the index case, basal LH
was 2.3 mIU/ml, and it was suggestive of activation of hypothalamo–pituitary–
gonadal (HPG) axis. Further, the stimulated LH value in the index child was
56.3 mIU/ml; however, the stimulation test was not warranted in our patient, and it is
only required if the basal LH is <0.3 mIU/ml. In addition, 17 β-estradiol cutoff of
80 pg/ml at 24h in response to GnRH agonist is also a surrogate indicator of activa-
tion of HPG-axis. The index child had stimulated 17 β-estradiol 185.3 pg/ml, further
supporting the diagnosis of GDPP. MR imaging of the brain is recommended in all
children with GDPP to localize any mass lesion in the hypothalamic region. The
probability of organic lesion is much higher in boys than in girls (40–90 % vs.
8–33 %) in children with GDPP. Further, the probability is much lower in girls
(approximately 2 %) when the puberty starts after the age of 6 years. In the index
case, MRI brain did not reveal any organic lesion; however, there was convexity of
the upper border of the pituitary gland (due to gonadotrope hyperplasia) suggestive
of GDPP. The indications for treatment in a child with idiopathic GDPP include rapid
progression of pubertal events over a period of 3–6 months (from one stage to the
next), significant advancement of bone age (>2.5 SD for chronological age), or pres-
ence of psychosocial concerns. However, all children with GDPP having organic
lesion must be treated irrespective of above mentioned criteria. The indication for