Overview.
Children whose height is less than 2 standard deviations or below the 3rd percentile of the average height of normal children of the same age and sex are often diagnosed as dwarfism due to various pathological factors. One of the common causes of childhood dwarfism is growth hormone deficiency (GHD). Growth hormone (GH) is an indispensable component of human growth, which mainly stimulates the secretion of insulin-like growth factor (IGF-1) in the liver, acting on bone and cartilage to cause height growth, and also promotes protein synthesis, fat decomposition, and regulates water and salt balance in the body to ensure human growth. It continues to play an important physiological and metabolic role after the epiphysis has healed and height growth has stopped.
There are various causes of growth hormone deficiency, including hypothalamic growth hormone secretion deficiency, pituitary gland pathology (e.g. congenital pituitary deficiency, tumor, trauma, radiation injury), central nervous system infection, and some genetic abnormalities. GH deficiency alone is called simple growth hormone deficiency; GH deficiency with other hormone deficiency is called multiple pituitary hormone deficiency, among which gonadotropin (GSH) deficiency is the most common, followed by thyrotropin (TSH) deficiency, and ACTH deficiency is the least common.
I. Diagnosis of growth hormone deficiency
Clinical manifestations Short stature is the most prominent manifestation of this disease. Generally, height and weight are normal at birth, but after 1 year of age, the growth rate is slowed down significantly, and the growth lag becomes more and more obvious as the age increases. Typical height is often more than 2 standard deviations lower than that of normal healthy children of the same age and sex, and adult height is extremely unsatisfactory, often 1.5 standard deviations lower than the average height of parents, and significantly lower than the average height of adults. The growth rate of height is less than 4~5 cm per year, the limbs are proportional, slightly fat, fat accumulation in the abdomen, round face, baby face, high pitched voice, delayed teething and ossification center development, bone age is often more than 2 years behind the actual age, and the intelligence is normal. A variety of pituitary hormone deficiencies have corresponding clinical manifestations.
If GH deficiency is accompanied by GSH deficiency, the child will still lack secondary sexual characteristics and the gonads will not develop in adulthood, and will eventually become infertile; if it is accompanied by TSH deficiency, the child may have a series of symptoms of hypothyroidism. Clinical manifestations include small appetite, immobility, rough skin, mucous edema, constipation, cold and unresponsiveness. Laboratory tests show a decrease in T4, but no increase in TSH. If GH deficiency is accompanied by ACTH deficiency, there may be hypoglycemia, hypotension, weakness and even fainting. Follow-up medical history may reveal hypoglycemia, delayed resolution of jaundice, small penis or intrapartum injury in individual children during the neonatal period.
Major special laboratory tests
As there are many pathological factors that may cause dwarfism in children, a comprehensive examination is needed to clarify the cause, such as bone age, trace elements, thyroid, liver and kidney function, blood and urine routine, blood glucose, insulin, lipids, IGF-1 and IGFBP-3, growth hormone stimulation test, sex hormone level, ultrasound, pituitary MRI, etc. In addition, karyotype analysis of chromosomes is needed for girls with dwarfism to exclude the possibility of Turner syndrome. For girls with short stature, karyotype analysis should be done to exclude the possibility of Turner syndrome.
In normal people, GH is secreted in a pulsatile manner. A random measurement of the basal value of GH is not clinically significant for diagnosing the lack of GH secretion in the pituitary gland. In the past, the physiological method of screening growth hormone, such as taking blood when the pituitary gland secretes GH after exercise or sleep, was used to measure GH, but it has been eliminated clinically because of the large error. Nowadays, the most commonly used method is to promote the increase of GH level in the body through drug stimulation test, and to observe the dynamic changes of GH in the blood through multiple spot blood sampling, so as to understand the ability of hypothalamus-pituitary gland to store, synthesize and secrete GH, and to clarify whether there is GH deficiency or not, which is a necessary test for the diagnosis of growth hormone deficiency.
The more commonly used stimulating drugs are arginine, colistin, levodopa, etc. If the peak value of GH is less than 10μg/L, the diagnosis of growth hormone deficiency can be confirmed. The test requires fasting blood, and it can be done after the child is about 4 years old, and the compliance is good!
IGF-1 and IGFBP-3 are useful for diagnosing abnormalities in the growth axis, with stable blood concentrations, the former correlated with age and nutritional status, the latter less so, and not affected by malnutrition. They are often used as screening tests for younger children and children with suspected growth hormone deficiency.
3.Bone age and MRI Bone age can reflect the developmental level of human from birth to full maturity, and is often used for the analysis and diagnosis of endocrine diseases, developmental and nutritional disorders, and genetic and metabolic diseases. In children with growth hormone deficiency, bone age is often more than 2 years behind the actual age. MRI (cranial magnetic resonance imaging) can help to detect intracranial tumors or congenital pituitary gland deficiency.
Diagnostic criteria for growth hormone deficiency
The diagnosis of growth hormone deficiency should first exclude other causes of short stature, such as Turner syndrome, hypothyroidism, chronic organic diseases and bone metabolic diseases. The current criteria for diagnosing growth hormone deficiency are:
1, height is less than 2 standard deviations from the average height of children of the same age and sex;
2, bone age is more than 2 years behind the actual age;
3, annual height growth < 4cm;
4, two drug stimulation test GH secretion peak less than 10μg/L ;
5.Proportional dwarfism, more subcutaneous fat in the abdomen, and normal intelligence.
IV. Treatment of growth hormone deficiency
Growth hormone deficiency is the absolute indication for GH therapy. From the pituitary-derived growth hormone in the 1950s to the genetically engineered in vitro recombinant human growth hormone (rhGH) in 1985, it has been in clinical use for more than half a century. In the past 30 years, with the continuous development of molecular biology technology, the current clinical application of rhGH and human GH structure is identical, high purity, good quality, by the application of millions of patients around the world, has not found any conclusive, serious side effects, under the guidance of physicians, routine side effects can also be avoided to ensure the safety of drug use.
For children diagnosed with growth hormone deficiency, the dose of rhGH should be 0.1~0.15 IU per kilogram of body weight per day, injected subcutaneously every night before bedtime, and can be used until epiphysis fusion. For those who have entered puberty and started treatment (especially those with low genetic height), it is generally recommended that the dose should be high, up to 0.15-0.2 IU per kg per day. The purpose is to imitate the normal high GH secretion during puberty and to overcome GH resistance that occurs in mid and late puberty, as well as to obtain the normal height gain during puberty.
The earlier the start of treatment, the longer the duration, the better the efficacy and the greater the help for lifelong height improvement. After treatment, there will be a catch-up growth, narrowing the height deviation with children of the same age. Generally clinical treatment can be started at the age of 4 weeks, and treatment needs to be started after the age of 2 years in severe cases!
3, follow-up monitoring, children with medication during the period, should be regular follow-up, measurement records height, weight changes, monitoring related growth indicators, in order to timely detection of problems, timely correction and adjustment of drug dose, to ensure the effectiveness of treatment.
(1) Thyroid function: Some children may have subclinical hypothyroidism after starting treatment, without obvious clinical manifestations, but in order to ensure the effect of GH treatment, thyroxine supplementation is needed to correct it in time.
(2) Blood IGF-1 and IGFBP-3 need to be monitored regularly during treatment to keep IGF-1 and IGFBP3 levels within a certain range, which is an effective indicator to ensure the efficacy and avoid side effects.
(3) Bone age: The bone age should be reviewed regularly every 6 months. Close monitoring is necessary for those who are nearing puberty and those who have already reached puberty.
In conclusion: Growth hormone deficiency is an absolute indication for recombinant human growth hormone, and a retrospective analysis of nearly 60 years of clinical use shows that it has a clear effect on improving the height of children with GHD, and long-term treatment is safe and effective without serious adverse side effects! Treatment under the guidance of a specialist and regular follow-up monitoring of relevant growth indicators can circumvent routine adverse effects and ensure the effectiveness of treatment. The earlier a child starts treatment, the better the results and the greater the improvement in lifelong height.