The child, female, 5 years and 6 months old, was admitted to the hospital on March 24, 2008.
On admission, the parents complained that they had found hard nodules in her bilateral breasts for 24 days.
II. Medical history
The development of breasts is a physical sign of the development of secondary sexual characteristics in females, therefore, the development of breasts indicates the initiation of pubertal development in females. Premature onset of sexual development is called precocious puberty. Precocious puberty is divided into central precocious puberty and peripheral precocious puberty, also known as true precocious puberty and pseudoprecocious puberty. For female breast development, central precocious puberty, i.e., true precocious puberty, is the main focus. The medical history should focus on the time of sexual development, the accompanying symptoms, and the triggers of the onset. Li Wenjing, Endocrine Genetic Metabolism Center, Beijing Children’s Hospital
(a) Further questioning content and purpose.
1. The time of the appearance of secondary sexual characteristics, as accurate as possible.
2. The speed of breast development, whether there is an increase in vulvar secretion, whether pubic hair and axillary hair appear, and whether there has been vaginal bleeding, in order to understand the process of sexual development.
3. Whether there is a history of estrogen exposure, such as birth control pills, cosmetics containing estrogen, health care drugs or food, in order to differentiate from pseudoprecocious puberty caused by exogenous drugs.
4. Whether there are neurological symptoms such as headache and vomiting, which can be used to distinguish central precocious puberty caused by central nervous system lesions.
5. Whether there are special dietary hobbies, such as drinking a lot of milk or yogurt daily; preferring fried food, especially fried chicken; and being addicted to certain beverages, etc. At present, it is observed that fried food, as well as the contamination of estrogen in food may be related to precocious puberty.
6. The timing of pubertal development of parents is used to identify familial precocious puberty. Mothers can be asked about the time of their first menstruation, while fathers can be asked about the time of their pubertal slam.
7.The parents’ height, which determines the genetic height of the affected child, is an important reference indicator for the treatment of this disease.
(ii) Inquiries about the results (medical history).
Twenty-four days before the child’s admission, his mother found about 1.0 cm × 1.0 cm hard nodules with tenderness in both breasts and white discharge from the vulva, which were not taken seriously and treated by the family. Twenty days before admission, the child still complained of breast tenderness, so she went to our outpatient clinic and had an ultrasound of the uterus and ovaries: the uterus was larger than that of a child of the same age, and one 0.4cm follicle and two 0.5cm follicles were seen in the ovaries. The sex hormones were basically normal: FSH: 0.4mIU/ml, LH: 0.4mIU/ml, E2: 7.2pg/ml, testosterone: <2ng/dl, pituitary prolactin: 4.1ng/ml, progesterone: 0.2ng/ml. 5 A-factors: T3: 212ng/dl, T4: 9.3ug/dl, FT3: 6.1pmol/L, FT4: 15.7pmol/L. She was admitted to the hospital as an outpatient with "cause of breast development to be investigated".
Since the onset of the disease, the child had no significant height growth acceleration, no headache, no nausea or vomiting, no menstrual flow, denied a history of misuse of contraceptive drugs, and had been taking protein powder, multi-dimensional nutrients and other nutritional drugs since September last year. She is a meat eater and does not like to eat vegetables.
Neonatal condition: full-term delivery, no history of intrauterine distress and postnatal asphyxia, healthy during the neonatal period.
The newborn was in good health during the neonatal period. His intellectual development was the same as that of a normal child of the same age. Her height is in the 75th percentile of the same age and sex, and her weight is between the 50th and 75th percentile of the same age and sex.
The father is 175 cm tall and his pubertal development is unknown.
The mother was 160 cm tall and had her first menstruation at the age of about 13 years.
Analysis of the findings (medical history): ① First, breast development suggests the beginning of pubertal development; there are nutritional drugs such as protein powder and multivitamin nutrients. The history of eating meat but not vegetables suggests the presence of nutritional factors that promote gonadal development. The increase in vulvar secretions suggests the influence of increased estrogen levels on the internal reproductive organs; ③ ultrasound shows ovarian follicles >0.4 cm in diameter, suggesting a tendency to develop germ cells; ④ normal thyroid function can exclude the presence of precocious puberty due to hypothyroidism; ⑥ pubertal growth is an important sign of pubertal development, the child may be in the early stage of pubertal development and needs to be observed for growth The growth rate should be observed. (7) There are no symptoms such as headache and vomiting, so we can initially exclude precocious puberty caused by intracranial lesions; (8) There is no history of misuse of drugs, so we can exclude precocious puberty caused by exogenous drugs; (9) Protein powder and nutrients may promote pubertal development; (10) Parents’ height determines the genetic target height of the child, which has a certain relationship with the treatment effect of the child.
Physical examination
(a) The content and purpose of the preliminary physical examination.
Height, description of the development of breast, pubic and axillary hair (according to Tanner’s staging), and the presence of milk coffee spots on the skin.
(ii) Physical examination findings.
Weight 19 kg Length 112 cm Height was between the 50th and 75th percentile for the same age and sex.
The physical examination showed that the child was well-nourished and well-proportioned. The skin and mucous membranes of the whole body did not show any rash, bleeding spots or milk coffee spots, the skin was elastic, the head was normal in appearance, and no special facial features were observed. There was no enlargement of the thyroid gland bilaterally.
Bilateral thorax was symmetrical, no deformity, breast development Tanner stage II, bilateral breast nuclei were about 1.0cm×1.0cm, darkened areola, soft to touch, no nodules and masses; no axillary hair, Tanner stage I. The breath sounds of both lungs were clear, the heart sounds were strong, the heart rhythm was uniform, and no obvious murmur was heard. The abdomen was soft, with no obvious masses and no pressure pain. There was no deformity of the skeletal spine of the limbs, and the muscle strength and tone were normal. Physiological reflexes were normally elicited and pathological reflexes were not elicited.
The vulva was seen to be plump with labia majora and uncolored labia minora; no pubic hair, Tanner stage I.
IV. Outpatient and external examination findings.
Cranial MRI findings showed no abnormality of the pituitary hypothalamus.
Orthopantomogram of the left hand and wrist: seven carpal bones were visible in the left wrist joint, and the distal ulnar epiphysis was not present.
Ultrasound of uterus and ovaries: the uterus is larger than that of the same age, one 0.4cm diameter follicle and two 0.5cm diameter follicles can be seen in the ovaries.
Sex hormones: FSH: 0.4mIU/ml, LH: 0.4mIU/ml, E2: 7.2pg/ml, testosterone <2ng/dl, pituitary prolactin: 4.1ng/ml, progesterone: 0.2ng/ml.
Analysis of physical and current examination results: ① The development of secondary sexual characteristics in girls starts before the age of 8 years and there is the development of secondary sexual characteristics caused by the initiation of hypothalamic-pituitary-gonadal axis (HPG axis) in order to be diagnosed as true precocious puberty or central precocious puberty. Pseudoprecocious puberty is the premature appearance of secondary sexual characteristics due to the spontaneous secretion of sex hormones, without the initiation of the HPG axis. In girls, only breast enlargement without the appearance of other secondary sexual characteristics before the age of 7 years is called premature breast development. The age of the child was 5 years and 9 months at the time of consultation, and the appearance of breast development can be diagnosed as early breast development, but whether it is true precocious puberty, the function of the hypothalamic pituitary gonadal axis (HPG axis) needs to be evaluated; ② the increase of vulvar discharge suggests the influence of estrogen on the internal reproductive organs, and the ultrasound shows follicles with diameter >0.4 cm in the ovaries indicating the tendency of gonadal development; ③ cranial MRI The normal results of cranial MRI can basically exclude central precocious puberty due to central nervous system lesions; ④ normal thyroid function can exclude pseudo-precocious puberty due to hypothyroidism; ⑤ since sex hormones are secreted in the human body in a pulsatile manner, normal sex hormone examination cannot exclude the diagnosis of precocious puberty.
Preliminary diagnosis: Premature breast development causes to be investigated: 1. idiopathic central precocious puberty; 2. simple precocious breast development; 3. pseudo-precocious puberty
VI. Preliminary treatment (admission to hospital)
No special treatment before the diagnosis of precocious puberty is confirmed.
VII. Further laboratory
(I) Content and purpose of further examination
1. Re-examination of bone age, sex hormones, pelvic ultrasound.
2.Gonadotropin-releasing hormone (LHRH) stimulation test to evaluate the hypothalamic pituitary gonadal axis.
(ii) Examination results.
1, pelvic ultrasound: left ovary: 1.7cm×1.1cm, intra-ovarian follicles: 0.5cm×0.5cm two. Right ovary: 1.8cm×1.1cm, intra-ovarian follicles: one 0.6cm×0.6cm and two 0.4cm×0.4cm. Impression: rapid growth of uterus, maximum follicle in ovary 0.6cm×0.6cm.
2. sex hormone 6 suggested slightly high FSH, the rest were normal.
3, Gonadotropin releasing hormone (GnRH) test.
The results returned: LH (0 points) <0.1mIU/ml, LH (30 points) 4.60mIU/ml, LH (60 points) 3.90mIU/ml, LH (90 points) 3.70mIU/ml; FSH (0 points) 1.60mIU/ml, FSH (30 points) 10.50mIU/ml, FSH (60 points) 14.40mIU /ml, FSH (90 points) 16.00mIU/ml. LH peak 4.60mIU/ml, FSH peak 16.00mIU/ml, LH/FSH = 0.29.
4. Bone age: 6-7 years.
VIII. Post-admission condition
There was no significant progressive breast enlargement after the child’s admission.
Analysis of laboratory findings: pelvic ultrasound showed rapid growth of uterus with >0.4 cm follicles, and elevated FSH level in sex hormone test, suggesting the possibility of precocious puberty due to elevated hormone level; GnRH test result showed peak LH <12 mIU/ml, LH/FSH = 0.29<1, which did not support the diagnosis of central precocious puberty due to activation of hypothalamic pituitary gonadal axis.
According to the examination results, further clarification or exclusion of diseases: observe the changes of breast development in the child: ① if the breast development regressed, no acceleration of bone growth, no progressive enlargement of uterus and follicles in ultrasound examination, it is possible that the child has simple premature breast development; ② if the child has progressive enlargement of breast development and acceleration of height growth, repeat GnRH stimulation test after 3-6 months The diagnosis of central precocious puberty is considered only if there is a suggestion of HPG axis initiation.
Diagnosis: 1. Early breast development. 2. Central precocious puberty?
Central precocious puberty cannot be excluded because of the early bone age and the presence of follicles larger than 0.4 CM on pelvic ultrasound. And there is no adverse effect of early breast development, if it is true precocious puberty, it may affect the lifelong height in adulthood.
X. Treatment
Because the child cannot be diagnosed as central precocious puberty yet, no special treatment is needed for the time being. However, regular outpatient follow-up should be carried out for the children and GnRH test should be repeated if necessary.
XI. About central precocious puberty
Precocious puberty refers to the presentation of secondary sexual characteristics before the age of 8 for girls and 9 for boys. Precocious puberty is divided into central (true) precocious puberty, pseudo precocious puberty and partial precocious puberty. Central precocious puberty (CPP) refers to the development of internal and external genitalia and the presentation of secondary sexual characteristics due to the premature secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus, which activates the hypothalamic pituitary gonadal axis and causes the pituitary gland to secrete gonadotropin, resulting in gonadal development.
(A) GnRHa application indications
1. In order to improve adult height, the following indications are recommended: (1) bone age: girls ≤ 11.5 years, boys ≤ 12.5 years, bone age is 2 years or more older than age; (2) predicted adult height: girls < 150 cm, boys < 160 cm; (3) bone age/age > 1, bone age/height age > 1, or standard deviation score (SDS) of height judged by bone age ≤ – 2; (4) rapid developmental process, bone age/age growth > 1. growth/ age growth > 1.
2. Indications for caution: GnRHa has poor efficacy in improving adult height and should be used with caution in the following cases: (1) bone age at the start of treatment: girls > 11.5 years, boys > 12.5 years; (2) pubic hair presentation; (3) target height is lower than the mean value of the normal height reference for the same sex and age minus 2 standard deviations.
3, should not be applied indications: GnRHa should not be applied in the following cases, because the treatment can hardly improve adult height; (1) bone age: girls ≥ 12. 5 years, boys ≥ 13. 5 years; (2) girls menarche or boys ejaculation after 1 year.
4. Indications not requiring application: CPP with little effect on adult height due to slow sexual developmental progression (bone age progression not exceeding age progression) does not require treatment, but requires periodic review of height and bone age changes.
(B) Application method
1. Dose: 80-100 μg/kg for the first dose and 60-80 μg/kg every 4 weeks thereafter; for those with advanced bone age of 12 years and follicle diameter close to 1 cm, a booster injection can be given 2 weeks after the first dose.
2. Treatment monitoring: Measure height and check paraphimosis every 2 to 3 months during treatment, and review the uterus and ovaries. Bone age should be checked every six months.
3.Course of treatment: In order to improve adult height, the course of GnRHa treatment needs at least 2 years. Generally, treatment can be stopped at the age of 12 to 12.5 years. For those who start treatment at a younger age, the drug can be stopped when the age has caught up with the bone age and the bone age has reached the normal age of puberty initiation, so that its gonadal axis function to restart.
4. Post-discontinuation monitoring: Height, weight and paraphimosis should be rechecked every six months for the first year after the end of treatment.
Comment: With the improvement of people’s living standard, the incidence of central precocious puberty (especially in girls) shows a trend of increasing year by year. Precocious puberty has no adverse effect on female reproductive function, but premature sexual development accelerates the pace of skeletal maturation and shortens the growth time, resulting in a portion of children with precocious puberty having lower lifelong height in adulthood than the normal population. The treatment of precocious puberty can prolong the growth time and improve the lifetime height of the child in adulthood. However, patients with central precocious puberty are difficult to distinguish from simple breast development in the early stages, even after LHRH stimulation test, but not in full certainty, so clinical follow-up is very important.