Autonomous gonadal activation

McCune–Albright syndrome and recurrent autonomous ovarian cysts due to somatic activating mutation of the GNAS gene resulting in increased signal transduction in the Gs pathway.

Mostly in girls. Typically rapid progression of breast development and early occurrence of vaginal bleeding (before or within a few months of breast development).

Precocious puberty may be isolated or associated with café-au-lait pigmented skin lesions or bone pain due to polyostotic fibrous dysplasia. More rarely other signs of endocrine hyperfunction (e.g. hypercortisolism, hyperthyroidism), liver cholestasis or cardiac rhythm abnormalities.

Typically large ovarian cyst or cysts on pelvic ultrasound examination.

Bone lesions of fibrous dysplasia.

May have laboratory evidence of hypercortisolism, hyperthyroidism, increased growth hormone secretion, hypophosphataemia, liver cholestasis.

Familial male-limited precocious puberty due to germinal activating mutations of the LH receptor gene.

A familial history of dominant precocious puberty limited to boys (but transmitted by mothers) may be present, but some cases are sporadic.

Activating mutation of the LH receptor gene.

Germline mutations of GNAS gene resulting in dual loss and gain of function (extremely rare)

Single case report of a boy with concomitant pseudohypoparathyroidism and gonadotropin-independent precocious puberty

Tumours

Granulosa cell tumours of the ovary

Rapid progression of breast development, abdominal pain may occur. The tumour may be palpable on abdominal examination

Tumour detection on ultrasound or CT scan

Androgen-producing ovarian tumours

Progressive virilization

Tumour detection on ultrasound or CT scan

Testicular Leydig cell tumours

Progressive virilization; testicular asymmetry (the tumour itself is rarely palpable)

Tumour detection on testicular ultrasound

hCG-producing tumours.

Tumours can originate in the liver or mediastinum. Pubertal symptoms in boys only. May be associated with Klinefelter syndrome

Elevated serum hCG

Adrenal disorders

Manifest with signs of androgen exposure

Congenital adrenal hyperplasia

Increased androgen production leading to virilization in boys and girls.

Increased adrenal steroid precursors in serum, mainly 17OH-progesterone (basal or after an ACTH stimulation test)

Adrenal tumour

Increased androgen production leading to virilization in boys and girls. Very rarely, oestrogen-producing adrenal tumour.

Tumour on abdominal ultrasound or CT scan.

Elevated DHEAS, or adrenal steroid precursors

Generalized glucocorticoid resistance

Symptoms and signs of mineralocorticoid excess, such as hypertension and hypokalaemic alkalosis

Elevated free urinary cortisol and plasma cortisol

Environmental agents

Exogenous sex steroids

Manifestations vary with the type of preparation (androgenic or oestrogenic); most commonly described after topical exposure to androgens; tracing the source of exposure may be difficult

Endocrine evaluation can be misleading due to widely variable serum levels of sex steroids with time

Exposure to oestrogenic endocrine-disrupting chemicals

May play a role in precocious puberty (by modulating the timing of pubertal gonadoptropic axis activation) although this remains unproven

No validated biochemical test

Severe untreated primary hypothyroidism

Signs of hypothyroidism. No increase of growth velocity.

Manifest mostly with increased testicular volume in the absence of virilization. Due to a cross-reactivity of elevated TSH to the FSH receptor.

Elevated serum TSH levels, low free T4 level.

No bone age advancement