Short stature refers to individuals of the same race, sex and age who are less than 2 standard deviations (-2SD) of the mean height of the normal population or less than the 3rd percentile (-1.88SD) in similar life circumstances, some of which are normal physiological variants. For proper diagnosis, appropriate clinical observations and laboratory tests must be performed in children with growth retardation.
I. 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 clarified so far.
Diagnosis
Children with short stature must be examined comprehensively to clarify the causes and facilitate treatment.
1. 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’ puberty development and the short stature in the family.
2.Physical examination
In addition to the routine physical examination, the following items should be measured and recorded correctly: current height and weight measurements and percentile; annual growth rate of height (at least 3 months of observation); target height measured from the parents’ height; BMI value; sexual developmental stages.
3.Laboratory tests:
(1) Routine examination
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.
(2) Bone Age (BA) determination
Bone age is the bone maturity at each age, and is determined by observing the growth and development of each ossification center in the left wrist, metacarpal and finger bones on the orthopantomograph. 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
Those whose height is lower than the normal reference value minus 2 SD (or lower than the 3rd percentile); those whose bone age is lower than the actual age by more than 2 years; those whose height growth rate is below the 25th percentile (according to bone age), i.e. <7 CM/rh for children <2 years old; those with clinical symptoms of endocrine disorders or dysmorphic syndrome; those who need pituitary function examination for other reasons.
(2) Growth hormone-insulin-like growth factor-1 axis (GH-IGF-1) function measurement
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.
(3) Measurement of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3)
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: subcutaneous rhGH injection at 0.075-0.15 U/(kg?d) every night for 1 week, blood samples were collected once before and once on the 5th and 8th day after the injection, and IGF-1 was measured; Method 2: subcutaneous rhGH at 0.3 U/(kg d) every night for 4 d, blood samples were collected once before and once after the last injection, and IGF-1 was measured. The serum IGF-1 of normal individuals will increase more than 3 times compared with its 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, other hormone options may be tested as needed.
(6) Imaging examination of hypothalamus and pituitary gland
MRI of the cranial region should be performed in children with short stature to exclude the possibility of congenital abnormalities or tumors.
(7) Karyotype analysis
Karyotype analysis should be performed in all children suspected of having chromosomal abnormalities.
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. We should also pay attention to the possibility of certain syndromes, such as Prader-Willi syndrome, Silver-Russeli syndrome, Noonan syndrome, etc.
Treatment:
1. The treatment measures for children with short stature depend on their etiology
The growth rate of children with psychosomatic and renal tubular acidosis will be increased after the related factors are eliminated, and the daily nutrition and sleep are closely related to the 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. 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, all younger children should be followed up regularly. In 2003, the FDA approved GH for idiopathic short stature, i.e.: non-GH deficiency of unknown origin; height below the normal reference value of 2.25 SD or more for children of the same sex and age; expected lifetime height in adulthood below -2SDS.
(1) Dosage form
There are two types of rhGH powder and water dose available in China, the latter has slightly better growth effect.
(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 0.1-0.15IU/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
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 degeneration of subcutaneous tissue due to repetition within a short period of time.
(4) Treatment course
The duration 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 their lifelong high effect is not great.
(5) Side effects
Common side effects are: hypothyroidism, which occurs every 2-3 months after the start of injections and can be corrected by giving L-thyroxine tablets as needed; 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. Antibody production: Due to the continuous improvement in the purity of the preparations, the rate of antibody production has been reduced, and the aqueous preparations are even less; femoral head slippage and necrosis: Because of the accelerated growth and muscle strength of the bones after treatment, increased movement can easily cause femoral head slippage, aseptic necrosis and lameness. Aseptic necrosis, lameness, knee and hip pain, external rotation pathology, temporary discontinuation of GH and supplementation of vitamin D and calcium tablets, injection of local redness or rash: usually disappears within a few days, can continue to use, is now rare, the possibility of tumor induction: international organizations have conducted relevant research studies, according to the National Cooperative Growth Group and Drug Therapy Research Center 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 caution is needed in the application of long-term supraphysiological doses of GH for children with previous tumors, genetic predisposition to family tumor occurrence, and malformation syndrome, and the treatment process should be The serum IGF-1 level should be closely monitored and should be temporarily discontinued for those who exceed the normal reference value +2SD.
3. Other drugs.
(1) Attention should be paid to the supplementation of calcium and trace elements for bone growth during the course of treatment.
(2) Anabolic hormone: often used in combination with growth hormone for the treatment of 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.
(3) IGF-1 gonadal axis inhibition (GnRHa), aromatase inhibitors (Letrozole, Letrozole), etc. 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.
V. Follow up
All children with diagnosed short stature should be followed up for a long time. For those who are treated with growth hormone, a follow-up visit should be conducted 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.