Premature puberty

Premature puberty (PPP) is a disorder of the development of the girl, manifested by one or all of the signs of puberty at the age of 2.5 or more standard deviations (2.5 SD or σ) below the average age of their appearance in the healthy children's population. Now in most countries of the world puberty is considered premature in the presence of any of its signs in girls of white race to 7 years and negroid race to 6 years of life.

[1], [2], [3]

Epidemiology

Premature puberty occurs in 0.5% of girls in the population. Among the entire gynecological pathology of childhood, premature puberty is 2.5-3.0%. In 90% of girls, the full form of premature puberty is due to the pathology of the central nervous system (CNS), including against the background of volumetric brain formations (45%). The McCune-Albright-Breitsev syndrome is found in 5%, estrogen-producing ovarian tumors - in 2.6% of girls with premature puberty. Premature bodily met in 1% of girls under the age of 3 years and it is 2-3 times higher than the frequency of true forms of premature puberty. The frequency of congenital hyperplasia of the adrenal cortex with a deficiency of 21-hydroxylase is 0.3% in the population of children under the age of 8 years.

[4], [5], [6], [7], [8], [9]

Causes of the premature puberty

HT-dependent premature puberty can be caused by a family predisposition (idiopathic variant), tumors or other pathological processes in the hypothalamic-pituitary region (cerebral variant). A rare cause of HT-dependent premature puberty is the inherited Russell-Silver syndrome, accompanied by moderately excessive production of gonadotropins from early childhood.

Premature puerache may be caused by excessive secretion of adrenal androgens in the nonclassical form of congenital adrenal cortex dysfunction, androgen-producing ovarian tumors (arrenoblastoma, lipid-cell tumor, gonadoblastoma, dysgerminoma, teratoma, choriocarcinoma) or adrenal glands (adenoma, androblastoma). Androgen-producing tumors of the adrenals and ovaries affect girls rarely.

Premature telarche and menarche (extremely rare) can occur with persistent follicular cysts, granulosa cell tumors of the ovaries, congenital and / or untreated hypothyroidism (Van Vika-Grombach syndrome), estrogen-producing tumors, chorionic gonadotropin and gonadotropins, and exogenous administration of estrogens and estrogen-like compounds in the form of dosage forms or with food products. HT-independent isosexual premature puberty occurs with McCune-Albright-Breitz syndrome, when premature telarche and menarche develop as a result of a congenital mutation of the receptor protein gene (GSα protein), which causes uncontrolled activation of the synthesis of estrogens.

In girls with partial premature puberty, spontaneous regression of secondary sexual characteristics is possible, and further development of the child occurs in accordance with age standards. On the other hand, the background state that caused the emergence of a secondary sexual sign can activate the hypothalamic structures by feedback and lead to complete premature puberty.

Forms

There is no officially accepted classification of premature puberty. Currently, gonadotropin-dependent (central or true) and gonadotropin-dependent (peripheral or false) premature puberty are isolated. According to ICD-10, gonadotropin-dependent (HT-dependent) premature puberty is designated as premature puberty of central origin. HT-dependent premature puberty is always complete, as it is manifested by all signs of puberty and accelerated closure of growth zones in girls under 8 years, while maintaining the physiological rate of maturation of other organs and systems.

Patients with HT-independent premature puberty according to the cause of the disease have isosexual or heterosexual manifestations. Partial GT-independent premature puberty is characterized by the premature development of one of the signs of puberty - the mammary glands (premature telarche), pubic haemorrhage (premature pu), menstruation (premature menarche), less often 2 symptoms (telarche and menarche).

Premature telaphae - one- or two-sided enlargement of the mammary glands to Ma2 by Tanner, more often the left breast. In this case, as a rule, there is no pigmentation of the areola of the nipples, there is no sexual hair and signs of estrogenation of the external and internal genital organs.

Premature puerpera - pubis hair in girls 6-8 years old, not combined with the development of other signs of puberty. If a preterm puarther appears in girls who have virilization of the external genitalia, it is referred to heterosexual gonadotropin-releasing hormone-independent premature puberty (GnRH-independent).

Premature menarche - the presence of cyclic uterine bleeding in girls under 10 years of age in the absence of other secondary sexual characteristics.

[10], [11], [12], [13]

Diagnostics of the premature puberty

The main goal of diagnosis of premature puberty:

• definition of the form of the disease (complete, partial);
• revealing the nature of the activation of premature puberty (GT-dependent and GT-independent);
• determination of the source of excessive secretion of gonadotropic and steroid hormones.

[14], [15], [16], [17], [18], [19]

Anamnesis and physical examination

Mandatory for all girls with any signs of premature puberty methods:

• anamnesis collection;
• Physical examination and comparison of the degree of physical and sexual maturation according to Tanner with age standards;
• measurement of blood pressure in girls with heterosexual premature puberty;
• clarification of the patient's psychological characteristics.

[20], [21], [22], [23], [24]

Laboratory methods

Determination of FSH, LH, prolactin, TTG, estradiol, testosterone, 17-hydroxyprogesterone (17-OP), dehydroepiandrosterone sulfate (DHEAS), cortisol, free T4 and free T3. A single determination of the level of LH and FSH is of little informative in the diagnosis of premature puberty.

Conducting samples that stimulate and suppress the production of steroid hormones

A sample with a synthetic analogue of GnRH is carried out in the morning hours after a full sleep. Since the secretion of gonadotropins has an impulsive character, the initial values of LH and FSH should be determined twice - 15 minutes and immediately before the administration of gonadoliberin. The basal concentration is calculated as the arithmetic mean of 2 measurements. The drug containing the GnRH analogue for daily use (tryptorelin) is injected rapidly once iv in a dose of 25-50 μg / m ² (usually 100 μg), followed by venous blood collection at 15, 30, 45, 60 and 90 min . Compare the baseline with any 3 highest stimulated values. The maximum increase in the level of LH is determined, as a rule, 30 minutes after the administration of the drug, FSH - after 60-90 minutes. Increase in the level of LH and FSH more than 10 times from the initial or to the values characteristic for the pubertal period, i.e. Exceeding 5-10 IU / l, indicates the development of full GT-dependent premature puberty. An increase in FSH levels while maintaining the minimum LH concentration in response to a trial with tryptorelin in patients with premature telaphah indicates a low probability of developing HT-dependent premature puberty. In children with other partial forms of premature puberty, the level of LH and FSH after the test is equal to that in children under the age of 8 years.

A small sample with glucocorticoids should be performed in girls with premature puartha if there is an increased content of 17-OP and / or DHEAS and testosterone in the venous blood. Preparations containing glucocorticoid hormones (dexamethasone, prednisolone) should be taken orally for 2 days. The daily dose of dexamethasone should be 40 μg / kg, and prednisolone in girls under 5 years - 10 mg / kg, 5-8 years - 15 mg / kg. When performing the sample, it is necessary to take venous blood in the morning on the eve of taking the drug and the morning of the third day (after the second day of admission). Normally, in response to taking the drug, there is a decrease in the level of 17-OP, DHEAS and testosterone by 50% or more. The lack of dynamics of hormone concentration suggests the presence of an androgen-producing tumor.

A sample with synthetic short-acting or prolonged-release ACTH (tetracosactide) is performed when a high plasma level of 17-OP, DHEAS and a reduced or normal level of cortisol is detected in order to exclude the nonclassical form of CSAH. The sample should be performed in a hospital environment, as a sharp increase in blood pressure and the development of allergic reactions after drug administration are possible. Tetrakosaktid [α- (1-24) -corticotropin] is administered at a dose of 0.25-1 mg p / c or IV immediately after venous blood sampling at 8-9 o'clock in the morning. When a short-lived drug is administered, the sample is evaluated after 30 and 60 minutes. After the introduction of tetracosactide prolonged action, repeated collection of venous blood is produced after at least 9 hours. When evaluating the results of the sample, the initial and stimulated levels of 17-OP and cortisol should be compared. In patients with premature puerperhosis, a nonclassical form of HBHC can be assumed with an increase in the initial level of 17-OP by 20-30% or more than 6 SD from the baseline level. The level of stimulated 17-OP, exceeding 51 nmol / l, is the most significant marker of the nonclassical form of CGNA. When carrying out a test with tetrakozaktidom prolonged action, you can focus on the index of discrimination:

D = [0.052 × (17-OP2)] + [0.005 × (K1) / (17-OP1)] - [0.018 × (K2) / (17-OP2),

Where D is the index of discrimination; K1 and 17-OP1 - the baseline level of cortisol and 17-OP-progesterone; K2 and 17-OP2 - the level of hormones 9 hours after the administration of tetracosactide. The diagnosis of a nonclassical deficiency of 21-hydroxylase is considered confirmed with a discrimination index exceeding 0.069.

Instrumental methods

• Echographic examination of internal genital organs with evaluation of the degree of maturity of the uterus and ovaries, mammary glands, thyroid and adrenal glands.
• Radiography of the left wrist and wrist joint with the definition of the degree of differentiation of the skeleton (biological age) of the child. Comparison of biological and chronological age.
• Electroencephalographic and echoencephalographic research with the detection of nonspecific changes (the appearance of a pathological rhythm, the irrigation of subcortical structures, increased convulsive readiness), most often accompanying premature puberty against the background of organic and functional disorders of the central nervous system.
• MRI of the brain in the T-2-weighted regimen is shown to all girls with the development of the mammary glands up to 8 years, the appearance of sexual embolism to 6 years with the estradiol level in the serum of more than 110 pmol / l in order to exclude the hamartoma and other volumetric formations of the third ventricle of the brain and pituitary gland. MRI of the retroperitoneal space and the adrenal gland is shown to girls with premature puartha.
• Biochemical study of the content of sodium, potassium, chlorine in venous blood in patients with signs of heterosexual premature puberty.

Additional Methods

• Cytogenetic study (definition of karyotype).
• Molecular genetic examination to identify specific defects of the activator gene of steroidogenesis enzymes (21-hydroxylase), the HLA system in girls with heterosexual premature puberty.
• Ophthalmic examination, including examination of the fundus, determination of acuity and visual fields in the presence of signs characteristic of the McCune-Albright-Breitsev syndrome.

[25], [26], [27], [28], [29],

Differential diagnosis

HT-dependent premature puberty

• Idiopathic (sporadic or familial) variant of the disease. In a family history, these children have indications of early or premature sexual development in relatives. Sexual maturation begins at a time close to the physiological, there is an early jump in the growth and development of the mammary glands. The pubertal values of LH, FSH, estradiol or pubertal response to stimulation of gonadotropin-releasing hormone in the absence of organic and functional CNS pathology.
• A non-tumoral variant of the disease is found in patients who had a history of indication of post traumatic (including birth trauma), post-inflammatory or congenital changes in the CNS; the transmitted infection in the prenatal period of life (cytomegalo- and herpes-viral infection, toxoplasmosis, syphilis, tuberculosis, sarcoidosis), in infancy and early childhood (meningitis, arachnoiditis, encephalitis, abscesses or granulomatous post-inflammatory processes). In the psychoneurological status there are signs of an organic psychosyndrome: increased excitability, emotional disinhibition. Neurological examination reveals symptoms of CNS lesion of a non-specific nature.
• Tumor variant of the disease is formed as a result of growth of the hypothalamic hamartoma, glioma, ependymoma, arachnoid or parasitic cyst of the ventricle III bottom, adenomas and cysts of the pituitary gland, pinealomas, very rarely against the background of the development of craniopharyngioma. A distinctive feature of most tumors is benign and slow growth in the cavity of the ventricle with limited contact with the wall of the third ventricle in the form of a narrow pedicle. Symptoms arising during the development of tumors are of the same type and are due to the attachment site, size and degree of disturbance of the outflow of the CSF. Tumors small in size, in addition to premature puberty, can clinically manifest themselves only with attacks of headaches with large light intervals. Children at the height of a headache attack are sometimes observed general weakness, pretentious posture due to decerebral rigidity, violent laughter (when the tumor is located close to the area that performs the motor regulation of laughter). Even more rarely observe epileptiform seizures with vasomotor disturbances and sensitive irritation (ostentatious tremor in the form of short-term paroxysms, profuse sweating, fever from subfebrile to 38-39 ° C, less often loss of consciousness and tonic convulsions). Mental disorders represent stiffness and apathy, but development of bouts of motor anxiety is possible.

A direct consequence of the hydrocephalic hypertensive syndrome is a variety of symptoms of loss of vision due to edema of the nipples, lesions of the intersection of the optic nerves or pathological irritation of the cranial, primarily oculomotor nerves (anisocoria, paresis of the gaze upward, etc.). Multiple gliomas, including those emanating from hypothalamic nuclei, can cause premature puberty in patients with neurofibromatosis (Recklinghausen's disease). This disease, inherited by autosomal dominant type, is characterized by multiple focal proliferation of clusters of neuroglia and fibrous tissue elements (appearing on the skin with smooth spots of coffee color or subcutaneous plaques). If one of the numerous neuroglyomas is located in the area of the clitoris, a false impression can be created about the masculinization of the external genitalia, i. E. About heterosexual premature puberty. As characteristic features note the spotting of the axillae and the multiplicity of visceral lesions. Since the first year of life, bone defects (cysts, curvatures) have been identified. Dumbbell-like thickening of the roots of the spinal nerves can cause intense pains that constrain the movement of the child. Cramps, visual impairment, mental retardation are possible. Premature puberty in children with neurofibromatosis develops as a true complete premature puberty in the first years of life.

In organic cerebral pathology, the symptoms of premature puberty usually appear later or simultaneously with the development of neurological symptoms. Often the coincidence in the time of onset of mammary gland growth and menarche GT-dependent premature puberty accompanies the emergence of all fully formed secondary sexual characteristics (M4-5 / P4-5 according to Tanner) and always ends with a premature menarche. The chronological age of the clinical debut of the disease ranges from 8 months to 6.5 years. Among all girls with HT-dependent premature puberty, only 1/3 retained the sequence and rates of puberty. In the first years of the development of the disease in the clinical picture, estrogen-dependent symptoms of puberty predominate in the absence of androgen-dependent symptoms (isosexual form). Mammary glands of a moderate degree of maturity (Ma2 according to Tanner), as a rule, appear in girls in 1-3 years of age simultaneously from both sides. Early onset and rapid progression of secondary sexual characteristics are characteristic of the hypothalamic hamartoma. In a number of girls, the disease, which began with the appearance of the mammary glands (premature telarche), may not appear for a long time with other signs of puberty. Incomplete form of HT-dependent premature puberty often remains until adrenarche (6-8 years), after which quickly (in 1 to 2 years) there are puubache and menarche. When hormonal examination, an increase in the content of estrogens is noted against the background of an increased initial and tryptorelin-stimulated level of gonadotropic hormones (LH, FSH). When HT-dependent premature puberty, the size of the uterus and ovaries (volume over 3 mm, multifallicular changes in the structure - the appearance of more than 6 follicles with a diameter of more than 4 mm) correspond to those of girls of pubertal age. In menstruating girls with premature puberty, the volume of both ovaries and the size of the uterus correspond to the sexually mature indices. In all patients with HT-dependent premature puberty, the accelerated development of the osseous system leads to an advance of the calendar age by bone age of 2 and more years and a rapid subsequent closure of the growth zones. At the beginning of puberty, these girls are significantly ahead of their peers in physical development, but already in adolescence they have a dysplastic physique due to short extremities and a wide bone pelvis, a long spine and a narrow shoulder girdle. The exception is girls with GT-dependent premature puberty in the Russell-Silver syndrome. This hereditary disease is characterized by intrauterine growth retardation, a violation of the formation of the skull bones (triangular face) and the skeleton (pronounced asymmetry of the trunk and limbs with low growth) in early childhood. The disease occurs with moderately excessive production of gonadotropins. Feminized newborns with this pathology have insufficient length and body weight (usually less than 2000 g) and lag behind their peers in growth at all stages of life. However, the bone and calendar age of these children is the same. The full form of premature puberty develops in girls with Russell-Silver syndrome to 5-6 years of age.

In girls with the full form of HT-dependent premature puberty, mental, emotional and intellectual development, despite external adulthood, corresponds to the calendar age.

Complete forms can occur in girls with HT-independent premature puberty, as well as after radiation and chemotherapy, or after surgical treatment of intracranial brain tumors.

[30], [31]

HT-independent premature puberty (isosexual)

Premature body. Selective breast enlargement is most common in girls under 3 and older than 6 years. As a rule, there are no pigmentation of the areola of the nipples, sexual hairs and signs of estrogenation of the external and internal genital organs. In the anamnesis of girls with premature corporal, as a rule, there is no data on gross pathology in the antenatal and postnatal periods. Physical development corresponds to age. Advancement of maturation of the osseous system does not exceed 1.5-2 years and does not progress further. In a number of cases, girls with premature telarche have episodic bursts of FSH and estradiol secretion on the background of the admissible level of LH. In girls with isolated premature telapha, in 60-70% of cases, follicles are encountered in the ovaries, sometimes reaching in the diameter of 0.5-1.5 cm. In the hormonal status of children, deviations from the normative for age of LH and FSH are most often absent. When tested with GnRH in girls with premature telarcheus, an increase in the level of FSH response is found in comparison with healthy contemporaries. The answer is that LG has an adjectival nature. The premature telarche does not accompany the acceleration of physical development. Usually, the mammary glands are independently reduced to normal sizes throughout the year, but in some cases remain enlarged until the puberty period. The instability of gonadotropic regulation can lead to the progression of sexual development in 10% of patients.

Premature menarche - the appearance of cyclic menstrual bleeding in girls under 10 years with no other secondary sexual characteristics. The causes of this condition are not specified. The study of anamnesis (the use of hormonal drugs, the ingestion of a large number of phytoestrogens) helps in the diagnosis. The growth and bone age of girls correspond to the calendar. During the examination, a transient increase in the level of estrogens is often detected during periods of acyclic blood discharge from the genital tract.

Premature puberty is more common in girls aged 6-8 years. The cause of premature isolated pu banga in girls may be excessive conversion of testosterone (even at normal values) to the active metabolite dehydrotestosterone in peripheral blood. Dehydrotestosterone breaks the natural rhythm of the development of the sebaceous-follicle follicle, keeping it in the stage of growth. Sexual and physical development of girls with increased activity of 5α-reductase does not differ from age standards. Perhaps a moderate increase in the clitoris, therefore, for a long time this form of premature puartha was designated as idiopathic or constitutional. Premature growth of pubic hair can be caused by increased peripheral formation of testosterone against a background of premature enhancement of adrenal androgen secretion. The marker of premature puartha is the increase in the level of DHEAS to puberty. Premature puerperas are referred to as non-progressive conditions that do not affect the rate of normal puberty. Bone age and growth almost always correspond to the calendar age, and if they are ahead of it, then no more than 2 years. Girls have no signs of estrogenic influence: glandular tissue of the mammary glands, the size of the internal genitalia corresponds to age. Hormonal parameters (gonadotropins, estradiol) correspond to those in prepubertal children, often the level of DHEAS in the serum is increased to pubertal values. When examining children with premature puarthache, the so-called nonclassical (late, postnatal, erased or pubertal) forms of CCHD are found. Premature puerbera often serves as the first marker of a number of metabolic disorders that lead to the development of metabolic syndrome in sexually mature women.

Van Vika-Grombach syndrome develops in children with decompensated primary hypothyroidism. The pronounced primary insufficiency of both thyroid hormones (thyroxin and triiodothyronine) causes a slowdown in growth, the appearance of a disproportionate physique and a lag in the development of the facial skeleton (wide sunken bridge of nose, underdevelopment of the lower jaw, large forehead, small fontanel enlargement). In the anamnesis of patients, late appearance and delayed teeth change are noted. Early symptoms of the disease are nonspecific, the child does not eat well, rarely cries, the jaundice remains longer in the newborn period, muscle lethargy, macroglossy, umbilical hernia, constipation, drowsiness. Later in the clinic of untreated patients there are lethargic tendon reflexes and a decrease in muscle strength, dry skin, bradycardia, hypotension, low rough voice, delayed psychomotor development and pronounced deviations of the intellect up to cretinism, obesity, myxedema. Bone age is 2 or more years ahead of the calendar year, and premature appearance of secondary sexual characteristics is noted. When hormonal examination reveals an increase in the secretion of prolactin, and in the ovaries are often found polycystic changes or the appearance of individual follicular cysts. It is much less common to develop sexual hair, and premature puberty becomes complete.

Premature puberty in the McCune-Albright-Breitsev syndrome usually begins with uterine bleeding, which occurs early (on average at 3 years) and long before the telarche and puarthache. Patients are characterized by the presence of asymmetric pigment spots on the skin, reminiscent of the geographical map of light-coffee color, multiple fibrocystic dysplasia of tubular bones and bones of the cranial vault. Often with this syndrome, the thyroid gland function (nodular goiter) is disrupted, acromegaly and hypercorticism are much less common. A characteristic feature of PPP against the background of the McCune-Albright-Breitsev syndrome is the wave-like course of the disease with a transient increase in serum estrogen levels to pubertal values with low (prebi) gonadotropin hormone (LH, FSH).

Estrogen-producing tumors (granulosa cell tumor, luteum), follicular cysts of the ovaries and adrenal glands. In childhood, the most common follicular cysts of the ovaries. The diameter of these cysts varies from 2.5 to 7 cm, but more often it is 3-4 cm. Against the background of the follicular cyst, clinical symptoms develop rapidly. Girls have pigmentation of areolas and nipples, the growth of mammary glands and uterus is accelerated, followed by the appearance of blood secretions from the genital tract without the development of sexual embryology. Often observed a noticeable acceleration of physical development. Follicular cysts can undergo independent reverse development within 1.5-2 months. With spontaneous regression or after removal of the cyst, a gradual decrease in the mammary glands and uterus is observed. However, with relapses or large cysts, changes in estrogenic influences can cause activation of the hypothalamic-pituitary region with the development of the full form of premature puberty. In contrast to premature puberty, which arose against the background of autonomic development of the follicular ovarian cyst, with true premature puberty, removal of the cyst does not allow to return the activity of the reproductive system to the level corresponding to the calendar age. Granulose-stromal-cell tumors, hyperplasia of the stroma and hypertecosis, teratoblastomas with elements of hormonal active tissue, chorionepithelioma, lipid-cell tumors of the ovaries are rare in girls, but they are the second most frequent cause of autonomic estrogen secretion, which can cause signs of premature puberty. In some cases, estrogens can secrete gonadoblastomas located in heavy gonads, cystadenomas and cystadenocarcinomas of the ovaries. Often the sequence of appearance of secondary sexual characteristics is distorted (premature menarche precedes telarche with timely pu). Uterine bleeding is predominantly acyclic, sexual pilosis is absent (at the initial stages) or weakly expressed. Clinical and laboratory examinations determine the increase in uterine size to mature, a one-sided increase in the size of the ovary or adrenal gland with a high level of estradiol in the serum of peripheral blood against the background of the tolerant values of gonadotropins. A distinctive feature of premature puberty, which arose against the background of estrogen-producing tumors, is the absence or insignificant advancing of biological (bone) age by calendar (no more than 2 years).

HT-independent premature puberty (heterosexual)

Premature puberty on the background of CGNA. Excessive production of androgens, especially androstenedione, causes virilization of the girls even in the prenatal period - from clitoral hypertrophy (stage I on Pradera) to the formation of a micropenia (stage V on the Pradera) with the urethra opening on the head of the clitoris / penis. Girls acquire heterosexual traits. The presence of a urogenital sinus that overlaps the deep vestibule of the vagina, a high perineum, and underdevelopment of small and large labia can lead to the fact that the child at birth is sometimes mistakenly recorded as a male sex with hypospadias and cryptorchidism. Even with pronounced masculinization, chromosomal recruitment in children with VGKN - chromosome 46 XX - and the development of the uterus and ovaries takes place in accordance with the genetic sex. At the age of 3-5 years, signs of heterosexual premature puberty are attached to the signs of congenital masculinization. Sexual embryology and acne on the skin of the face and back appear. Under the excessive influence of androgenic steroids, mainly DHEAS, a growth jump corresponds to the size of a pubertal growth jump, but by the age of 10 the patients cease to grow because of the complete fusion of epiphyseal fissures. The disproportion of physical development is expressed by short stature due to short massive limbs. In contrast to girls with HT-dependent PPS, also having a low growth, patients with premature puberty on the background of CGPN reveal masculine features of a physique (broad shoulder girdle and a narrow funnel-shaped basin). Anabolic action of DHEAS and androstenedione leads to densification of adipose tissue and muscle hypertrophy. The girls look like "little Hercules". Progressive virilization is accompanied by the growth of hair on the face and limbs, along the midline of the abdomen and back, the voice becomes rough, the cricoid cartilage increases. The mammary glands are not developed, the internal genitalia remain stably of a preubertal size. The clinical picture is dominated by androgen-dependent signs of puberty. The presence in the family of brothers with premature puberty or sisters with clinical manifestations of virilization, as well as indications of masculinization of the external genitalia from the neonatal period, suggests the CGAP. In cases of detection of premature sexual feeding in combination with other signs of virilization in girls with heterosexual premature puberty, it is necessary to clarify the type of enzyme defect. In the classical form of HSCH associated with a deficiency of 21-hydroxylase, the basal level of 17-OP and adrenal androgens, especially androstenedione, increases at a normal or elevated level of testosterone and DHEAS and a low level of cortisol. The pronounced deficiency of 21-hydroxylase leads to a significant limitation of the synthesis of both deoxycortisol and deoxycorticosterone, which in turn causes the development of clinical manifestations of aldosterone deficiency. The lack of mineral corticoids causes an early development of the salt-losing form of HSCH caused by a significant deficiency of 21-hydroxylase (Debreu-Phibiger syndrome).

For the timely detection of this form of CGPN in girls with heterosexual HT-independent premature puberty, it is necessary to measure blood pressure, and when it is increased - to study the content of potassium, sodium and chlorine in the blood plasma. One of the first clinical symptoms of nonclassical variants of CGAP is the accelerated puarthache. Echographic examination allows detecting bilateral adrenal enlargement, insignificant in the nonclassical form, or essential in the classical version, exceeding the age standards. If there is a difficulty in interpreting the basal level of steroid hormones (moderate increase in the level of 17-OP and DHEAS in the blood serum), a sample with synthetic ACTH (tetracosactide) is performed in patients with a presumed nonclassical variant of CCHP. An in-depth genetic examination with HLA-typing allows to specify the genetic sex of the child, confirm the diagnosis of CCHD, reveal the girl's belonging to hetero- or homozygous carriers of the defect and predict the risk of recurrence of the disease in offspring.

Premature sexual maturation against the background of an androgen-producing ovarian tumor (arenoblastoma, teratoma) or adrenal gland. The peculiarity of this form of premature puberty is the steady progression of the symptoms of hyperandrogenemia (premature adrenarche, greasiness of the skin and scalp, multiple simple acne on the face, back, barifony, pronounced odor of sweat). An androgen-producing tumor of the ovaries or adrenal glands should be excluded in the first place in patients with premature puberty having a rapid increase in the clitoris in the absence of symptoms of virilization at the time of birth. The sequence of appearance of secondary sexual characteristics is disrupted, menarche, as a rule, is absent. With ultrasound and MRI of the retroperitoneum and pelvic organs, one of the ovaries or adrenal glands is found to increase. The preserved daily rhythm of steroid secretion (cortisol, 17-OP, testosterone, DHEAS), determined in the blood serum (at 8 h and 23 h), allows to exclude autonomous production of steroids by the adrenal glands. Hormonal research indicates that the level of androgenic steroids (testosterone, androstenedione, 17-hydroxyprogesterone, DHEAS) is tens of times higher than age standards.

Treatment of the premature puberty

The goal of treatment of HT-dependent premature puberty:

• Regression of secondary sexual characteristics, suppression of menstrual function in girls.
• Suppression of accelerated rates of bone maturation and an improvement in the prognosis of growth.

Medical therapy with HT-independent forms of premature puberty caused by persisting for more than 3 months follicular cysts or hormone-producing tumors of the ovaries or adrenal glands, as well as for intracranial tumors (except hypothalamic hamartoma) has not been developed. The main method of therapy is surgical treatment.

Indications for hospitalization

• For the surgical treatment of volumetric brain formations in a specialized hospital of the neurosurgical profile.
• For the surgical treatment of bulk formations of the adrenal glands, hormonal-active formations of the ovaries and liver.
• To conduct a sample with tetracosactide (ACTH).

Non-drug treatment

Data confirming the advisability of non-drug therapy in detecting volumetric CNS formations (except for the hypothalamic hamartoma), hormonal-active tumors of the adrenal glands, ovaries, and follicular ovarian cysts persisting for more than 3 months are absent.

Medication

The main pathogenetically justified type of drug therapy for HT-dependent premature puberty is the use of long-acting analogues of GnRH, which promote rapid desensitization of gonadotrophs of the pituitary gland, decrease in the level of gonadotropins and, ultimately, decrease in the level of sex steroids. Therapy with GnRH analogues is performed in children with HT-dependent premature puberty with rapid progression of clinical manifestations of the disease (acceleration of bone age more than 2 years and acceleration of growth rate more than 2 SD), with the appearance of other signs of puberty in children with partial forms of HT-independent premature puberty, with repeated menstruation in girls under the age of 7 years.

The use of GnRH agonists to improve the final prognosis of growth is advisable for bone age not older than 11.5-12 years. The effect of agonist therapy after ossification of growth zones (12-12.5 years) is not only weakly expressed, but also may be unfavorable.

In children with a body weight of more than 30 kg, a full dose of 3.75 mg is used, with a body weight below 30 kg, a half dose of triptorelin or buserelin. The drug is administered / m once every 28 days until the age of 8-9 years. Perhaps the transnazal use of a short-lived analogue of GnRH - buserelin. The daily dose is 900 μg for children weighing more than 30 kg or 450 μg with a mass below 30 kg (1 injection 3 times a day); if the symptoms of premature puberty do not stop, then it is possible to increase the daily dose to 1350 mcg or 900 mcg (2 injections 3 times a day) according to the weight of the child's body. Reliable positive dynamics of clinical symptoms of the disease is noted during the first 6 months of therapy. The control of the effectiveness of therapy is carried out 3-4 months after its beginning by repeated testing with GnRH agonists. Therapy is reversible. An increase in the level of gonadotropins and sex hormones to baseline values occurs 3 to 12 months after the last injection, the restoration of menstrual function in girls - 0.5-2 years after discontinuation of treatment. With prolonged use in rare cases, it is possible to damage the epiphyses of the femurs.

Progestogens (medroxyprogesterone, cyproterone) are used to prevent uterine bleeding against the background of progressive HT-independent premature puberty. The therapeutic effect is due to anti-estrogenic effect on the endometrium with a weak effect on the symptoms of puberty. In the treatment of true puberty, the effectiveness is low. Medroxyprogesterone in a daily dose of 100-200 mg / m ² is administered / m 2 times a week. With prolonged use, it is possible to develop symptoms of hypercorticism, which is due to some glucocorticoid activity of the progestogen. The daily dose of cyproterone is 70-150 mg / m ². Prolonged use of the drug contributes only to the delay of bone maturation, without affecting the final prognosis of growth, but can lead to a weakening of resistance to stress due to oppression of the secretion of glucocorticoids in the adrenal cortex.

Premature isolated body

Data confirming the advisability of drug treatment with premature teleraphy are absent. An annual observation and temporary abstinence from vaccinations in girls with a premature telaler are shown, given the possibility of breast enlargement after their implementation.

With an isolated teloparch against a background of a diminished thyroid function, Van-Vika-Grombach syndrome shows pathogenetic substitution therapy with thyroid hormones. According to the international standard, the calculation of the daily dose is carried out taking into account the surface area of the body (PPT), which is calculated by the formula: PPT = M ^0.425 × P ^0.725 × 71.84 × 10 ^-4,

Where M is the mass of the body, kg; P - growth, see In this calculation, the daily dose of levothyroxine sodium in children under 1 year is 15-20 μg / m ², over 10 years - 10-15 μg / m ². Levotiroksin sodium is used continuously - in the morning on an empty stomach 30 minutes before meals under the control of the level of TSH and free thyroxine (T4) in the serum at least once in 3-6 months. The criteria for adequacy of treatment are the normal indices of TSH and T4, the normal dynamics of growth and inhibition of bone age, the disappearance of blood from the genital tract, the reverse development of secondary sexual characteristics, the absence of constipation, the restoration of the pulse and the normalization of mental development.

Premature puerbha

Data confirming the advisability of drug treatment with premature puartha are absent. Carry out preventive measures aimed at forming a stereotype of healthy nutrition and preventing weight gain:

• Reduction in the diet of foods high in refined carbohydrates and saturated fats. The total amount of fats in the daily ration should not exceed 30%;
• struggle with hypodynamia and maintenance of a normal mass-growth ratio with the help of regular physical exercises;
• the exclusion of mental and physical loads in the evening hours, the observance of the duration of a night's sleep not less than 8 hours.

McCune-Albright-Breitsev Syndrome

Pathogenetic therapy is not developed. With frequent and massive bleeding, it is possible to use cyproterone. The daily dose of cis-proton acetate is 70-150 mg / m ². Cyproterone acetate has an antiproliferative effect on the endometrium, which leads to the termination of menstruation, but does not prevent the formation of ovarian cysts. With recurrent follicular cysts of the ovaries, tamoxifen is used in a daily dose of 10-30 mg, which is capable of binding nuclear receptors and controlling the content of estrogens in patients with McCune-Albright-Breitz syndrome. Use of the drug for more than 12 months promotes the development of leukopenia, thrombocytopenia, hypercalcemia, changes in the tone of small vessels and, as a consequence, the development of retinopathy. An alternative medicamentous effect is the use of the aromatase inhibitor of the first generation of testolactone. The mechanism of action of the drug is reduced to the suppression of aromatase and, as a consequence, a decrease in the conversion of androstenedione to estrone and testosterone to estradiol. The drug is highly toxic, therefore its use in children is limited.

HT-independent premature puberty (heterosexual)

In the heterosexual type of premature puberty on the background of CGPN without signs of loss of salt, treatment that started before the age of 7 is most effective. When treating children with CGAP, the use of long-acting drugs (dexamethasone) should be avoided and the dose of the drug used equivalent to hydrocortisone should be calculated. Initial daily doses of glucocorticoids should be 2 times higher than the dose of cortisone, which provides complete suppression of ACTH production. For girls under 2 years, the initial daily doses of prednisolone are 7.5 mg / m ², at the age of 2-6 years - 10-20 mg / m ², over 6 years - 20 mg / m ². The maintenance daily dose of prednisolone for girls under 6 years is 5 mg / m ², over 6 years - 5-7.5 mg / m ². Currently, hydrocortisone is the drug of choice in the treatment of the viral form of CGAP in girls over 1 year old. He is prescribed in a daily dose of 15 mg / m ² in 2 divided doses in girls under 6 and 10 mg / m ² in girls over 6 years of age. For maximum suppression of ACTH secretion, glucocorticoids should be taken after meals, with plenty of fluids, 2/3 of the daily dose in the morning and 1/3 of the dose at bedtime for life. The dose of glucocorticoids is reduced gradually only after the normalization of laboratory indicators. Control of the minimally effective maintenance dose of glucocorticoids is carried out according to the level of 17-OP and cortisol in the blood taken at 8 am, and mineralocorticoids by the blood renin activity. With closed growth zones, hydrocortisone should be replaced with prednisolone (4 mg / m ² ) or dexamethasone (0.3 mg / m ² ). It is important to pay special attention to the girl's relatives that, on the background of stress, acute illness, surgical intervention, climate change, fatigue, poisoning and other stressful situations, a doubled dose of the drug should be taken. It is necessary to offer relatives to buy a bracelet for the girl, indicating the diagnosis and the most effective dose of hydrocortisone, which should be administered in life-threatening cases.

In the heterosexual type of premature puberty against the background of congenital hyperplasia, the adrenal cortex with signs of loss of salt in infancy and with the salt-losing form of CGAP are recommended to use fludrocortisone, which is the only synthetic glucocorticoid for replacing mineralocorticoid insufficiency. Therapy is performed taking into account the activity of renin plasma. The initial daily dose of the drug is 0.3 mg. The whole daily dose should be taken in the first half of the day. Then, within a few months, the daily dose is reduced to 0.05-0.1 mg. The maintenance daily dose for children under 1 year is 0.1-0.2 mg, over 1 year - 0.05-0.1 mg. In cases of moderate and severe disease, the combined administration of hydrocortisone in the 15-20 mg tablets together with 0.1 mg of fludrocortisone is recommended in the morning, and after lunch - only hydrocortisone in a dose of 5-10 mg. In the daily diet of girls with a salt form of CGAP, it is necessary to include 2-4 g of table salt.

In the heterosexual type of premature puberty against the background of congenital hyperplasia of the adrenal cortex with secondary activation of the hypothalamic-pituitary-ovarian system, glucocorticoids should be combined with GnRH analogues - triptorelin or buserelin at a dose of 3.75 mg intramuscularly once in 28 days to the age of 8-9 years.

Surgery

Surgical methods of treatment are used in children with premature puberty, developing against the background of hormone-active tumors of the adrenal glands, ovaries, and also bulk CNS formations, however, removal of the tumor does not lead to regress of premature puberty. Hypothalamic hamartoma is removed only by strict neurosurgical indications. Estrogen-producing follicular ovarian cysts that persist for more than 3 months are subject to compulsory surgical removal. Surgical treatment is used if there is a need for correction of the structure of the external genitalia in girls with heterosexual premature puberty in the background of CCHD. Penis-like or hypertrophic clitoris should be removed immediately after diagnosis, regardless of the child's age. The dissection of the urogenital sinus is more expedient to conduct after the appearance of signs of estrogenization of the genital organs - at 10-11 years. Long-term use of glucocorticoids and natural estrogenic influences contribute to the loosening of the perineal tissue, which greatly facilitates the operation of forming the entrance to the vagina.

Indications for consultation of other specialists

• Consultation of a neurosurgeon in case of detection of volumetric CNS formations to decide the feasibility of surgical treatment.
• Consultation of the endocrinologist to clarify the functional state of the thyroid gland in patients with clinical signs of hypothyroidism, hyperthyroidism, diffuse enlargement of the thyroid gland; in addition, all patients with McCune-Albright-Breitsev syndrome to exclude the concomitant pathology of the endocrine system.
• Consultation of a neurologist to clarify the neurological status of patients with central forms of premature puberty in the absence of organic pathology of the central nervous system.
• Consultation of the oncologist with suspicion of malignancy of volumetric formation of ovaries or adrenals.

Further management of the patient

Regardless of the type of medication, the adherence to the principle of continuity and duration of therapy is recognized as a prerequisite for the successful therapeutic effect of true or secondary complete GT-independent premature puberty, since the abolition of treatment after 3-4 months causes the disappearance of gonadotropic suppression and the resumption of puberty. Therapy should be performed until the age of not less than 8-9 years. After the abolition of treatment, girls should be registered at the children's gynecologist before the end of sexual development. All children with a diagnosis of premature puberty require a dynamic observation (at least once every 3-6 months) before and during the entire period of the physiological pubertal period. The determination of bone age is carried out in girls with any form of premature puberty once a year. Girls receiving GnRH should be observed 1 time in 3-4 months before puberty stops completely (normalization of growth rate, decrease or stop of development of mammary glands, suppression of LH synthesis, FSH). The test with GnRH should be performed in the observation dynamics for the first time after 3-4 months of therapy, then once a year.

Prevention

There are no data confirming the availability of developed measures to prevent premature puberty in girls.

[32], [33], [34], [35]

Forecast

In premature puberty, a growing malignant tumor of the brain, ovaries and adrenal glands can lead to death.

A significant improvement in the prognosis of growth in patients with any form of premature puberty at an early onset of therapy was noted. Late diagnostics and untimely started treatment significantly worsen the prognosis of growth in patients with HT-dependent premature puberty and provoke the transformation of the disease into full form with partial GT-independent premature puberty.

In patients with neoplasms, the prognosis for life is unfavorable, which is due to a high percentage of malignant germ cell-cell tumors. Irradiation of tumors of intracranial localization can lead to the development of pituitary insufficiency followed by endocrine disorders that require appropriate methods of endocrine rehabilitation.

Premature telaphae only in 10% of cases is transformed into true premature puberty.

There is no reliable data on fertility and reproductive health in women with a history of premature puberty.

[36], [37], [38]