Definition of short stature.
Short stature is defined as individuals of the same race, sex and age whose height is 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, and for proper diagnosis, appropriate clinical observations and laboratory tests must be performed in children with growth retardation.
Etiology.
There are many factors leading to short stature, including many interactions, and there are also many diseases leading to short stature whose mechanisms have not been elucidated so far Cranio-cerebral injuries.
Perinatal injuries (breech birth, ischemia and hypoxia, intracranial hemorrhage, etc.); skull base fractures, radiation injuries, inflammatory sequelae, etc.
Cerebral infiltrative lesions.
E.g., tumors, Langerhans cell histiocytosis bullosa, etc.
Other.
Smaller than fetal age children, neurosecretory dysfunction of growth hormone, psychosomatic short stature, chromosomal aberrations, skeletal development disorders, chronic systemic diseases, etc.
Diagnosis.
A comprehensive examination must be performed in children with short stature to clarify the cause in order to facilitate treatment.
I. Medical history.
Careful inquiries should be made about: pregnancy of the affected mother; birth history of the affected child; birth length and weight; growth history; pubertal development of the parents and short stature in the family, etc.
II. Physical examination.
In addition to the routine physical examination, the following items should be correctly measured and recorded: ① the measured value and percentile of current height and weight; ② the annual growth rate of height (at least 3 months of observation); ③ the target height measured from the height of his/her parents; ④ the BMI value; ⑤ the stage of sexual development.
III. Laboratory tests.
1. Routine examination: blood and urine tests and liver and kidney function tests should be routinely performed; blood gas and electrolyte analysis should be performed for suspected renal tubular toxicity; karyotype analysis should be performed for girls; to exclude subclinical hypothyroidism, thyroid hormone levels should be routinely tested.
2.Bone Age (BA) determination: the development of bones throughout the growth and development process, is a good indicator to assess the development of the organism, bone age is the age of bone maturity, is the left wrist, metacarpal, finger bone orthopantomographs to observe the growth and development of its various ossification centers to determine. 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); ② those whose bone age is lower than the actual age by more than 2 years; ③ those whose height growth rate is below the 25th percentile (according to bone age), i.e.: <7 CM/rh for children <2 years old; ④ those with clinical symptoms of endocrine disorders or deformity syndrome; ⑤ those who need pituitary function for other reasons (2) Growth hormone - pancreatic hormone
(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 1).
(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, 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. Method 1: 0,075-0,15 U/(kg/d) of rhGH was injected subcutaneously 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: 0,3 U/(kg?d) of rhGH was injected subcutaneously every night for 4 days, and blood samples were collected once before and once after the last injection to determine IGF-1. The serum IGF-1 of normal individuals will increase more than 3 times its basal value after injection, or reach the normal value corresponding to their age.
(5) Testing of other endocrine hormones: Based on the clinical manifestations of the child, other hormone choices of the child may be tested as needed.
(6) Imaging of hypothalamus and pituitary gland: MRI of the skull 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 differentiated, 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.Treatment measures for children with short stature depend on their etiology: children with psychosomatic and renal tubular acidosis will see an increase in their height growth rate after the relevant factors are eliminated, and daily nutrition and sleep security 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. In 2003, the FDA approved GH for idiopathic short stature, i.e.: (1) those with unknown causes of non-GH deficiency; (2) those whose height is lower than the normal reference value of 2,25 SD or more for children of the same sex and age; (3) those whose lifetime height is expected to be below -2SDS in adulthood.
(1) Dosage: There are two kinds of rhGH powder and water dose available in China, and the latter has slightly better growth effect.
(2), Dose: The dose range of growth hormone is large 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, 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: The WHO labeled growth hormone 1J=30. WHO labeled growth hormone 1J=30U).
(3) Usage: 1 subcutaneous injection every night before bedtime, the usual injection site is the outer and anterior side of the middle 1/2 of the thigh, and the injection site should be changed for each injection to avoid the denaturation 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 role is not great.
(5) Side effects: The common side effects are: ① Hypothyroidism: It often 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 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. Idiopathic intracranial pressure elevation, peripheral edema and blood pressure elevation may occur in individual patients, mostly in children with chronic renal failure, Turner syndrome and growth disorders due to GH deficiency. ④Antibody production: Due to the continuous improvement of preparation purity, the rate of antibody production has now 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, increased movement may cause femoral head slippage, aseptic necrosis, cause claudication, 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 it is rare now. (7) Possibility of tumor induction: International organizations have conducted relevant research studies. According to a large amount of epidemiological data from academic institutions such as National Cooperative Growth Group and 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 applying long-term supraphysiological dose of GH.
3, other drugs: ① during the course of treatment should pay attention to calcium, trace elements and other supplements for bone growth; ② anabolic hormone: often used 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 no sufficient data to analyze in China, so it is not recommended for routine application.
Follow up.
All children diagnosed with short stature should have long-term follow-up: those treated with growth hormone should be followed up once every 3 months: height measurement (preferably SSDS) and here also IGF-1, IGFBP-3, T4, TSH, blood glucose and insulin tests for timely adjustment of GH dose and thyroid hormone supplementation. 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.