Short stature refers to individuals of the same race, sex and age whose height is less than 2 standard deviations (-2SD) from the mean height of the normal population or less than the 3rd percentile (-1.88SD) in a similar living environment, some of which are normal physiological variants. For proper diagnosis, appropriate clinical observations and laboratory tests must be performed on children with growth retardation.
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 mother’s pregnancy, birth history, birth length and weight, growth history, parents’ puberty and short stature in the family, etc. should be carefully inquired.
Physical examination
In addition to the routine physical examination, the following items should be measured and recorded correctly.
① The measured value and percentile of current height and weight.
② Annual growth rate of height (at least 3 months of observation).
③ target height measured from their parents’ height.
④BMI value.
⑤ Sexual development staging.
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 all girls; thyroid hormone levels should be routinely tested to exclude subclinical hypothyroidism.
Bone Age (BA) is a good indicator for assessing 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 orthogonal 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) Those whose height is lower than the normal reference value minus 2 SD (or lower than the 3rd percentile).
(ii) Those whose bone age is more than 2 years below the actual age.
③ height growth rate below the 25th percentile (by bone age), i.e., <7CM/rh for children <2 years old.
④ those with clinical symptoms of endocrine disorders or dysmorphic syndrome manifestations.
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 such as exercise and sleep, which were used in the past, are rarely used nowadays, 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) 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 suspected of GH resistance (Laron syndrome), this test can be used to detect GH receptor function.
(1) Method 1: subcutaneous injection of rhGH at 0.075-0.15 U/(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.
(2) Method 2: subcutaneous rhGH at 0.3 U/(kg?d) every night for 4 days, blood samples were collected once before and once after the last injection, and IGF-1 was measured.
(5) Testing of other endocrine hormones Depending on the clinical manifestations of the child, the child’s other hormone choices may be tested 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, clinical attention should be paid to the possibility of certain syndromes, such as Prader-Willi syndrome, Silver-Russeli syndrome, Noonan syndrome, etc.
Treatment
1.Treatment measures for children with short stature depend on their etiology Psycho-psychological and renal tubular acidosis, etc. After the relevant factors are eliminated, their height growth rate will be increased, and the daily nutrition and sleep guarantee 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 followed up regularly. 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.
(ii) whose height is 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 the latter has a slightly better growth effect.
(2) Dose The dose of growth hormone ranges widely and should be adjusted individually 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, Turner children, children younger than fetal age, 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: The WHO labeled growth hormone 1J=30). WHO labeled growth hormone 1J=30U)
(3) Usage: Subcutaneous injection is given once a night before bedtime, and the usual injection site is the outer and anterior side of the middle 1/2 of the thigh.
(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.
(i) Hypothyroidism: occurs every 2-3 months after the start of the 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 develop idiopathic intracranial pressure elevation, peripheral edema and elevated blood pressure, which mostly occurs in children with chronic renal failure, Turner syndrome and GH deficiency-induced growth disorders.
(iv) Antibody production: the rate of antibody production has now been reduced due to the continuous improvement in the purity of preparations, and even less in aqueous preparations.
⑤ slippage and necrosis of femoral head: because the growth of bones is accelerated and muscle strength is increased after treatment, it is easy to cause slippage and aseptic necrosis of femoral head and cause claudication when there is increased movement, and pain in knee and hip joints may also occur with external rotation pathology, which can be temporarily discontinued with GH and supplemented with vitamin D and calcium tablets ⑥ local redness or rash of injection: it usually disappears within a few days and can be continued, which is now rare
(vii) 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 Drug Therapy Research Center, including 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, serum IGF-1 level should be closely monitored during treatment, and those who exceed the normal reference value +2SD should be temporarily stopped.
3. Other drugs.
(i) Attention should be paid to the supplementation of calcium and trace elements for bone growth during the course of treatment.
②Anabolic hormone: often used in combination with growth hormone for the treatment of Turner syndrome, most domestic use stanozolol (Conilon), the common dose is 0.025-0.05J/(K.d) need to pay attention to the growth of bone age.
③ IGF-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) and IGF-1, IGFBP-3, T4, TSH, blood glucose and insulin tests should be performed here to adjust GH dose and thyroid hormone supplementation 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.