[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. For proper diagnosis, appropriate clinical observation and laboratory tests must be performed on children with growth retardation.
【Etiology】.
1. Common disease dwarfism: malnutrition dwarfism, growth hormone deficiency, congenital ovarian hypoplasia, and chondrodysplasia. The common feature of these diseases is slow growth, and the annual height value is lower than the standard of the same age, and they will be half a head shorter than the children in the same class in kindergarten (5-10 cm), and the height gap with the same age will gradually increase with age.
2.Non-disease dwarfism: Low birth weight children, premature children, children less than gestational age, familial dwarfism, and somatic growth retardation are non-disease dwarfism, whose common feature is that they are often short at birth, but their growth rate is normal and their height is always lower than normal.
3. Precocious puberty: we call it precocious puberty when sexual signs appear before the age of 8 for girls and 9 for boys, or when menstruation appears before the age of 10 for girls. Such children have accelerated skeletal growth and early epiphyseal closure. Although they are temporarily taller than other children of the same age, they tend to be shorter than normal in adulthood.
Diagnosis
Children with short stature must be examined thoroughly to clarify the cause for treatment.
I. Medical history
The following should be carefully asked: the pregnancy of the mother of the child; the birth history of the child; the birth length and weight; the history of growth and development; the parents’ youth development and short stature in the family.
Physical examination
In addition to the routine physical examination, the following items should be measured and recorded correctly: (1) the measurement of current height and weight; (2) the target height measured from the height of the parents; (3) the sexual developmental stage.
Laboratory examination
Routine blood and urine tests and liver and kidney function tests should be routinely performed; karyotype analysis should be performed 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;
③Height growth rate below the 25th percentile (according to bone age), i.e. <7CM/rh for children <2 years old;
(4) Those with clinical symptoms of endocrine disorders or dysmorphic syndrome;
(5) Those who need pituitary function examination for other reasons.
(2) Growth hormone stimulation test The physiological screening tests such as exercise and sleep that were used in the past are rarely used now, and most of them are directly used for drug stimulation test.
(3) Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) determination The serum concentration of both increases with age and developmental process, and is 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 was injected subcutaneously at 0.075-0.15U/(kg・d) every night for 1 week, and blood samples were collected once before and once on the 5th and 8th day after the injection to determine IGF-1;
Method 2: Subcutaneous rhGH was administered at 0.3 U/(kg・d) every night for 4 days, and blood samples were collected once before and once after the last injection for the determination of IGF-1.
(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 children suspected of having chromosomal aberrations.
[Differential diagnosis
Based on medical history, physical examination and other data analysis, it is easier to identify short stature caused by malnutrition, psychosomatic family idiopathic short stature, less than fetal age children, chronic systemic diseases and other factors that are not growth hormone deficiency. The common causes of short stature should be identified, such as chondrodysplasia, hypothyroidism, and delayed somatic puberty; clinical attention should also be paid to the possibility of certain syndromes, such as Prader-Willi syndrome, Silver-Russeli syndrome, Noonan syndrome, etc.
Treatment
1.Therapeutic measures for children with short stature depend on their etiology Psycho-psychological and renal tubular acidosis children will see an increase in their height growth rate after the relevant factors are eliminated, and the guarantee of daily nutrition and sleep is 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 below the normal reference value of 2.25 SD or more for children of the same sex and age;
(③) expected to have a lifetime height of -2SDS or less in adulthood.
(1) Dosage form Two kinds of rhGH powder and water are available in China, and powder is the main dosage form.
(2) Dose The dose of growth hormone has a wide range and should be adjusted individually according to the need and the observed efficacy. At present, the commonly used dose in China is 0.15-0.2IU/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: Inject subcutaneously once a night before bedtime, the usual injection site is around the navel, and the injection site should be changed for each injection to avoid the degeneration of subcutaneous tissue due to repetition within a short period of time.
(4) Course of treatment: 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: The common side effects are.
① Hypothyroidism: Occurs 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 large amounts of growth hormone may cause insulin resistance 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;
⑤ Femoral head slippage and necrosis: because of the accelerated growth and muscle strength of the bones after treatment, it is easy to cause femoral head slippage, aseptic necrosis and lameness when there is increased movement, and also knee and hip pain with external rotation 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 now it is rare
(7) GH treatment does not increase the risk of leukemia occurrence and tumor recurrence, but caution is needed for the application of long-term supraphysiological doses of GH for those who have had tumors, have family genetic predisposition for tumor occurrence, and malformation syndrome.
3.Other drugs.
①The supplementation of calcium and trace elements should be paid attention to during the course of treatment for bone growth;
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 every 3 months. Those treated with growth hormone should be followed up once every 3 months: height measurement, IGF-1, IGFBP-3, T4, TSH, blood glucose and insulin tests should be performed here, so that the GH dose and thyroxine 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.