The Endocrine Genetic Metabolism Group of the Pediatrics Branch of the Chinese Medical Association had proposed the clinical application of genetically recombinant human growth hormone in 1998 (Chinese Journal of Pediatrics, 1997.37:234). On this basis, an extensive and in-depth discussion on the diagnosis and treatment of children with short stature was conducted again in October 2006, and a consensus was reached, which is now synthesized as follows for the reference of clinical workers.
Definition of short stature]
Short stature refers to individuals of the same race, sex and age whose height is lower than the average height of the normal population by 2 standard deviations (-2SD) or lower than the 3rd percentile (-1.88SD) in a similar living environment, some of which are normal physiological variants, and for proper diagnosis, children with growth retardation must undergo appropriate clinical observation and laboratory tests.
Etiology
There are many factors leading to short stature, including many interactions, and the mechanism of short stature caused by many diseases has not been elucidated so far (see Table 1)
Diagnosis
Children with short stature must be examined thoroughly to clarify the cause for treatment.
I. Medical history
The following should be carefully investigated: the pregnancy of the child’s mother; the birth history of the child; the birth length and weight; the history of growth and development; the parents’ pubertal development and the short stature in the family.
Physical examination
In addition to the routine physical examination, the following items should be measured and recorded correctly.
① Current height and weight measurement values and percentile;
(2) Annual growth rate of height (at least 3 months of observation); (3) Target height measured from parents’ height; (4) BMI value; (5) Sexual development stage.
III. Laboratory tests
Blood and urine tests and liver and kidney function tests should be routinely performed; blood gas and electrolyte analysis are recommended for suspected renal tubular toxicity; karyotype analysis is required for girls; to exclude subclinical hypothyroidism, thyroid hormone levels should be routinely tested.
Bone Age (BA) is a good indicator to assess the development of an organism. Bone age is the maturity of bone at each age, and is determined by observing the growth and development of each ossification center on ortho-X-rays of the left wrist, palm and finger bones. The most used methods at home and abroad are the G-P method (Greulich & Pyle) and the TW3 method (Tanner-Whitehouse), and the G-P method is mostly used in our clinic. Under normal circumstances, the difference between bone age and actual age should be between ±1 year, and being too far behind or too far ahead is considered abnormal.
3.Special examination
(1) Indications for special examination
(1) The height is lower than the normal reference value minus 2 SD (or lower than the 3rd percentile);
②Bone age below the actual age of 2 years or more;
(3) Height growth rate below the 25th percentile (based on bone age), i.e. <7CM/rh for children <2 years old; (4) Clinical symptoms of endocrine disorders or dysmorphic syndrome;
(5) Those who need pituitary function examination for other reasons.
(2) Growth hormone-insulin-like growth factor-1 axis (GH-IGF-1) function determination The physiological screening tests used in the past, such as exercise and sleep, are rarely used now, and most of them directly use drug stimulation tests (see Table 2).
(3) Measurement of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) The serum concentrations of both increase with age and development, and are related to nutrition and other factors, so each laboratory should establish its own reference data.
(4) IGF-1 production test For children with suspected GH resistance (Laron syndrome), this test can be used to detect GH receptor function.
Method 1: rhGH is injected subcutaneously at 0.075-0.15U/(kg・d) every night for 1 week, and blood samples are collected once before and once on the 5th and 8th day after the injection to determine IGF-1;
②Method
The serum IGF-1 of normal individuals will increase more than 3 times the basal value after injection, or reach the normal value corresponding to their age.
(5) Testing of other endocrine hormones Depending on the clinical manifestations of the child, testing of other hormone choices of the child can be performed as needed
(6) Imaging of hypothalamus and pituitary gland MRI should be performed in children with short stature to exclude the possibility of congenital developmental abnormalities or tumors.
(7) Karyotype analysis Karyotype analysis should be performed in all children suspected of having chromosomal aberrations.
[Differential diagnosis
Based on medical history and physical examination, it is easy to identify short stature caused by malnutrition, psychosomatic family idiopathic short stature, small for gestational age, chronic systemic diseases, etc. The common causes of short stature should be identified, such as chondrodysplasia, hypothyroidism, and delayed somatic puberty. In addition, some syndromes, such as Prader-Willi syndrome, Silver-Russeli syndrome, Noonan syndrome, etc., should be identified.
Treatment
1.Treatment measures for children with short stature depend on their etiology Psychosomatic, renal tubular acidosis and other children will see an increase in their height growth rate after the relevant factors are eliminated, and daily nutrition and sleep protection are closely related to normal growth and development.
2.Growth hormone With the accumulation of experience in the clinical application of recombinant human growth hormone (rhGH), the number of diseases approved for treatment with rhGH has gradually increased. Prader-Willi syndrome (2000), small for gestational age (2001), and idiopathic short stature (2003).
Since most children younger than gestational age show catch-up growth in the first 2-3 years of life and can reach a growth curve proportional to their target height, they should be regularly followed up and observed. Generally, GH treatment should be considered at 3 weeks of age if their growth is still lagging. 2003 FDA approved GH for idiopathic short stature, namely.
(i) those with non-GH deficiency of unknown origin;
②Height is below the normal reference value of 2.25 SD or more for children of the same sex and age;
(③) their lifetime height in adulthood is expected to be -2SDS or less.
(1)Dosage form
There are two types of rhGH powder and water dose available in China, and the latter has a slightly better growth effect.
(2)Dose
The dose of growth hormone has a wide range and should be individually adjusted according to the need and the observed efficacy. At present, the commonly used dose in China is 0.1-0.15IU/kg・d, 0.23-0.35mg/kg per week; for children with pubertal development, children with Turner, children younger than fetal age, children with idiopathic short stature and some children with partial growth hormone deficiency, the applied dose is 0.15-0.20IU/(K.d), 0.35-0.46(J.K) per week (Note: WHO labeled growth hormone 1J=30). WHO labeled growth hormone 1J=30U)
(3) Usage.
The usual injection site is the outer and anterior flank of the middle 1/2 of the thigh, and the injection site should be changed each time to avoid the denaturation of subcutaneous tissue due to repetition within a short period of time.
(4) Treatment course.
The course of growth hormone treatment for short stature depends on the need, usually should not be shorter than 1-2 years, too short when the child’s benefit to its lifelong high effect is not great.
(5) Side effects.
Common side effects are.
① Hypothyroidism: Occurs every 2-3 months after the start of injection and can be corrected by giving L-thyroxine tablets as needed;
② Altered glucose metabolism: Long-term use of larger amounts of growth hormone may cause insulin resistance to occur in children. Fasting blood glucose and insulin levels may rise, but rarely exceed the normal high limit, and may recover after several months of growth hormone discontinuation;
(iii) Idiopathic benign intracranial pressure elevation: Growth hormone can cause nadir and water retention, and individual patients may experience idiopathic intracranial pressure elevation, peripheral edema and blood pressure elevation, which mostly occurs in children with chronic renal failure, Turner syndrome and GH deficiency-induced growth disorders;
④Antibody production: Due to the continuous improvement of preparation purity, the rate of antibody production has been reduced, and even less for aqueous preparations;
⑤ Femoral head slippage and necrosis: because the growth of bones is accelerated and muscle strength is increased after treatment, the increased movement is likely to cause femoral head slippage, aseptic necrosis and lameness, and also knee and hip pain, which is externally rotated pathology, GH can be temporarily discontinued and treated with vitamin D and calcium tablets
(6) Local redness or rash of injection: usually disappears within a few days and can be continued, but it is now rare.
(7) The possibility of tumor induction: International organizations have conducted relevant research studies, and according to a large amount of epidemiological data from academic institutions such as the National Cooperative Growth Group and the Center for Drug Therapy Research, including a comprehensive analysis of population information such as age, gender and race of tumor patients, the results show that GH treatment does not increase the risk of leukemia occurrence and tumor recurrence in children without the presence of potential tumor risk factors, but for However, for those who have had tumor, have family genetic tendency of tumor occurrence, malformation syndrome, caution is needed when long-term supraphysiological dose of GH is applied, and serum IGF-1 level should be closely monitored during treatment, and those who exceed the normal reference value +2SD should be temporarily discontinued.
3. Other drugs.
①The supplementation of calcium and trace elements should be paid attention to during the course of treatment for the bone growth required;
②Anabolic hormone: often used with growth hormone to treat Turner syndrome, most domestic use stanozolol (Conilon), the common dose of 0.025-0.05J/(K.d) need to pay attention to the growth of bone age;
③IGF-1 gonadal axis inhibition (GnRHa), aromatase inhibitors (Letrozole, Letrozole) have also been used to treat short stature, but there is not enough information to analyze in China, so it is not recommended for routine application.
Follow-up]
All children diagnosed with short stature should be followed up once every 3 months. Those who are treated with growth hormone should be followed up once every 3 months: height measurement (SSDS measurement is best), IGF-1, IGFBP-3, T4, TSH, blood glucose and insulin tests should be performed here, so that the GH dose and thyroid hormone supplementation can be adjusted in time. Bone age should be checked once a year. Sexual development should be observed during the course of treatment and treated as needed. Regular repeat cranial MRI scans should be noted for suspected intracranial lesions.