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Central precocious puberty
Central precocious puberty (CPP), also referred to as gonadotropin dependent precocious puberty, is an endocrine-related developmental disease characterized by the onset of pubertal changes, with development of secondary sexual characteristics and accelerated growth and bone maturation, before the normal age of puberty (8 years in girls and 9 years in boys).
ORPHA:759Classification level: Disorder
The prevalence of CPP has been evaluated at approximately 1/ 500 girls and 1/ 2,000 boys in Denmark. Girls are more affected than boys, with an overall male to female ratio of at least 1:10.
CPP can have a progressive or a non progressive course. In progressive CPP (40% of cases), pubertal changes include acceleration of growth and bone maturation, premature unilateral or bilateral breast development leading to early menarche in girls, and testicular and penile enlargement with development of facial and sexual hair in boys. Pubic and axillary hair growth can be observed. In non-progressive CPP (rather referred to as non progressive PP), pubertal changes either do not progress or regress after a few months, and growth acceleration and bone maturation are not observed.
CPP is due to premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. It is idiopathic or secondary to hypothalamic lesions such as tumors (hypothalamic hamartoma, glioma, astrocytoma), CNS infections (meningitis, encephalitis) (see these terms), brain malformations (hydrocephalus, arachnoid cysts), trauma and injuries. Some cases of CPP have been linked to mutations in the imprinted makorin ring finger 3 MKRN3(15q11.2) gene that has a potential inhibitory effect on gonadotropin releasing-hormone (GnRH) secretion and a very limited number of cases have been reported which seem to be linked to mutations in the KiSS-1 metastasis-suppressor KISS1 (1q32) and kisspeptin-receptor KISS1R (19p13.3) genes.
Diagnosis is suspected upon physical examination and pelvic ultrasonography showing increased uterine length and increased uterine and ovarian volume in girls. It is confirmed by screening of basal luteinizing hormone LH levels (<0.1 IU/l being indicative of a prepubertal stage, 1 to 2 IU/l indicative of progressive CPP), and measurement of gonadotropin levels after stimulation tests using gonadotropin releasing hormone (GnRH) or its analog (GnRHa) leuprolide.
Differential diagnosis includes gonadotropin-independent precocious puberty (including familial male-limited precocious puberty, McCune-Albright syndrome (see these terms)), gonadal tumours, and benign premature thelarche or pubarche.
Most cases are sporadic. Familial cases show an autosomal dominant mode of transmission with incomplete, gender-dependent penetrance. The MKRN3 gene is imprinted and mutations causing CPP have been parternally inherited so far.
Management and treatment
Non progressive PP does not require therapy. Treatment of progressive CPP relies on the use of GnRH agonists (leuprorelin, triptorelin, histrelin). Puberty-related signs subsequently regress rapidly and adult size is usually improved. Treatments are interrupted around the normal age of pubertal development.
CPP can have a psychological effect during childhood. The disease has minimal consequence during adulthood, although the association of variation of pubertal timing with adult disease or behavior has been questioned.