Guidelines for the diagnosis and treatment of short stature
—Endocrine Genetic Metabolism Group of the Pediatric Branch of the Chinese Medical Association (organized by Shen Yonian and Wang Muti) Hu Xiaorong, Department of Pediatrics, Nantong First People’s Hospital
The Endocrine Genetic Metabolism Group of the Pediatrics Branch of the Chinese Medical Association proposed the clinical application of recombinant human growth hormone in 1998 (Chinese Journal of Pediatrics, 1999, 37; 234), and on this basis, the diagnosis and treatment of children with short stature were discussed extensively and thoroughly again in October 2006. June 2008, Vol. 46, No. 6. (hereinafter referred to as “Guidelines”)
In order to facilitate parents’ knowledge about short stature, we would like to highlight the questions that parents usually care about for brief reading.
I. What is short stature? Where to check if your child is short?
According to the Guidelines, short stature refers to individuals of the same race, sex and age who are below the mean height of -2 SD or the 3rd percentile (-1.88 SD) of the normal population in a similar living environment. The guidelines also emphasize that because some short stature is a normal physiological variation. In order to make a correct diagnosis, appropriate clinical observations and laboratory tests must be performed in children with growth retardation.
Parents should observe their children’s growth rate every year. The guideline points out that if the growth is less than 5cm/year from the age of 4 to prepubertal; and less than 6cm/year during puberty, the child should be taken to the pediatric endocrinology department (or pediatrics) of the hospital for timely consultation, and the younger the treatment age, the better the efficacy.
Second, what are the causes of short stature?
The Guidelines point out that there are many factors leading to short stature, including many interactions, and many mechanisms are not yet clear. The Guide classifies the causes of short stature into the following categories: the first category is non-endocrine defective short stature, and idiopathic short stature belongs to this category; the second category is growth hormone defect, and GHD and Laron syndrome belong to this category; in addition, there are short stature caused by craniocerebral injury and brain infiltration lesion; children younger than fetal age, Turner syndrome, chondrodysplasia, chronic renal failure short stature, precocious puberty, etc. All are classified as others.
What examinations are needed to detect short stature in children?
The Guidelines point out that children with short stature must be examined comprehensively to clarify the causes and facilitate treatment. In addition to routine physical examination, the measured values and percentile of height and weight, annual growth rate of height, and sexual developmental stages should be correctly recorded and measured.
Routine laboratory tests should include routine blood and urine tests and liver and kidney function tests; blood ammonia and electrolyte analysis should be performed in suspected renal tubular acidosis; karyotype analysis should be performed routinely in girls; thyroid hormones should be routinely tested to exclude subclinical hypothyroidism.
3. Special examination The Guidelines point out that: those whose height is lower than the normal reference value-2SD (or lower than the third percentile) and whose bone age is lower than the actual age by more than 2 years should undergo further experimental examination
Bone age determination Bone age is a good indicator to assess biological development throughout the growth and development process. Orthopantomographs of the left wrist, palm and finger bones were taken to observe the growth and development of each ossification center. Under normal circumstances, the difference between bone age and actual age should be between +1 year, and being too far behind or ahead is considered abnormal.
Growth hormone (GH) stimulation test: Nowadays, the drug stimulation test is mostly used directly, and the commonly used drugs are insulin, arginine, colistin, levodopa and GHRH (generally not used for diagnosis.) A GH peak of <5μg/L during the drug stimulation test is considered a complete deficiency of growth hormone; between 5μg and 10μg/L is a partial deficiency; >10μg/L can exclude GHD. Since there is a 15% false-positive rate for either stimulation test (meaning low GH secretion), the diagnosis of GHD must be confirmed when both stimulation tests are abnormal, and currently two drug tests with different modes of action, such as insulin and colistin or levodopa, are mostly chosen. The insulin test is not only reliable, but can also measure hypothalamic D pituitary D adrenal axis function at the same time. Since the pituitary function of children with GHD due to hypothalamic lesions is normal, GHRH can induce the pituitary gland to secrete GH normally, therefore, GHRH test is generally not used for diagnosis, but is often used to distinguish whether the lesion is in the hypothalamus or pituitary gland.
Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein (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.
IGF-1 production test: In children with suspected GH resistance (Laron syndrome), this test can be used to detect GH receptor function. Method 1: rhgh was injected subcutaneously at 0.075-0.15 U/(kg.d) every night for 1 week, and blood samples were collected once before the injection and once on the 5th and 8th day after the injection to determine IGF-1; Method 2: rhgh was injected subcutaneously at 0.3 U/(kg.d) every night for 4 d, and blood samples were collected once before the injection and once after the last injection to determine IGF-1. serum IGF-1 in normal subjects was higher than their basal IGF-1. 1 will increase more than 3 times its basal value after injection, or reach a normal value corresponding to its age.
Testing of other endocrine hormones: Depending on the clinical presentation of the child, the child’s choice of its chemical hormones may be tested as needed.
Imaging of hypothalamus and pituitary gland: MRI of the skull should be performed in all children with short stature to exclude the possibility of congenital developmental abnormalities or tumors.
Karyotype analysis: Karyotype analysis should be performed in all children suspected of having chromosomal aberrations.
IV. After these tests, how should dwarfism be treated?
The Guide points out that since 1985, when the FDA approved recombinant human growth hormone (rhgh) for the treatment of growth hormone deficiency, the following have been approved: chronic renal failure (1993), congenital ovarian hypoplasia (1996-1997), Prader-willi syndrome (2000), small for gestational age children (2001) and idiopathic short stature ( 2003).
Two domestic options are available, rhgh powder and water, with the Guidelines noting that the latter has a slightly better growth effect. The dose of growth hormone has a wide range and should be adjusted individually according to the need and the observed efficacy of delivery.
The commonly used dose in China is 0.1~0.15U/(kg.d) (0.23~0.35mg/kg per week)
The dose should be 0.15-0.20U/(kg.d) (0.35-0.46mg/kg/week) for children with pubertal growth, Turner’s children, children younger than fetal age, children with idiopathic short stature and certain partial growth hormone deficiencies.
The usual injection site is the middle 1/2 of the thigh and the anterior flank, 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.
V. How long is the treatment course of growth hormone application?
The Guidelines state that the duration of growth hormone treatment for short stature depends on the need, and should not be shorter than 1-2 years.
Will growth hormone treatment have side effects? Will it cause tumors?
According to the Guidelines, common side effects of growth hormone are: local redness, swelling, or rash of the injection: usually disappear within a few days and can be continued. They are now rare. Hypothyroidism: Occurs 2 to 3 months after the start of injection and can be corrected with L-thyroxine tablets as needed; altered glucose metabolism: Long-term, high doses of growth hormone may cause insulin resistance in children, with increased fasting glucose and insulin levels, but rarely above the normal high limit. Idiopathic benign intracranial pressure elevation: Growth hormone can cause nadir and water retention, and individual cases of idiopathic intracranial pressure elevation, peripheral edema and blood pressure elevation may occur, mostly in children with chronic renal failure, Turner syndrome and growth disorders due to GH deficiency. Antibody production:Due to the continuous improvement of preparation purity, the rate of antibody production has been reduced for the powder and even less occurs for the aqueous agent. Slippage and necrosis of femoral head:The growth of epiphysis is accelerated and muscle strength is increased after treatment, and the increased movement is likely to cause slippage and aseptic necrosis of femoral head, resulting in claudication, which may cause knee and hip pain, and may be treated by suspending GH and supplementing with vitamin D and calcium.
Potential for tumor induction.
The Guidelines state that GH treatment does not increase the risk of leukemia development and tumor recurrence in children without the presence of potential tumor risk factors
For children with previous tumors, genetic predisposition to family tumor occurrence, and malformation syndrome, caution is needed when long-term supraphysiologic doses of GH are applied, and serum IGF-1 levels should be closely monitored during treatment, and temporary discontinuation is appropriate for those exceeding the normal reference value +2SD.
What else should I pay attention to during the treatment process?
The Guidelines state that: All children diagnosed with short stature should be followed up and reviewed for a long time. Those who are treated with growth hormone should be reviewed every 3 months: height measurement to assess growth rate, IGF-1, IGFBP-3, T4, TSH, blood glucose and insulin testing to facilitate 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