I. Growth Hormone Deficiency
GHD is the first disease approved by the US FDA to be treated with rhGH. Since there is no gold standard for the diagnosis of GHD, the growth indicators and biochemical test results of the children should be analyzed in the process of diagnosis.
The diagnosis of GHD is based on: ① height lagging behind the 3rd percentile (minus 1.88 standard deviation or two standard deviations) of normal healthy children of the same age and sex; ② annual growth rate <7cm/year (under 3 years old); <5cm/year (3 years old ~ pre-pubertal); <6cm/year (puberty); ③ uniform short stature and infantile face; ④ normal intellectual development; ⑤ bone age lagging behind (6) peak GH levels in both GH drug-induced tests were <10ug/L; (7) serum insulin-like growth factor 1 (IGF1) levels were lower than normal.
GH drug provocation test is currently an important basis for clinical diagnosis of GHD. Although there is a 15% false-positive rate for any of the excitation tests, GHD can only be diagnosed when the results of two drug excitation tests (two drugs with different mechanisms of action) are abnormal, but the test still has certain limitations, and it is difficult to be used as the gold standard for GHD diagnosis. For example, the GH excitation test cannot reflect the GH secretion in physiological state; the repeatability and accuracy of the test are not good, and there are many factors affecting the results of the GH excitation test, such as the excitation drug, GH testing method and sexual development status; moreover, the diagnostic threshold of GH peak in the GH excitation test is artificially set, and the peak is affected by age, gender, pubertal development and the excitation drug. The GH peak in the GH stimulation test is affected by age, sex, pubertal development and stimulating drugs.
Serum IGF1 was once considered as a screening indicator for GHD because it has no obvious pulsatile secretion and circadian pattern, is relatively stable, and can better reflect the endogenous GH secretion status. However, IGF1 is influenced by gender, age, puberty, nutritional status and genetic factors, and it is appropriate for each laboratory to establish its own corresponding normal reference value. reduced IGF1 level can be considered as a possible GHD, but normal IGF1 level cannot completely exclude GHD. reduced IGFBP3 level is helpful for the diagnosis of children with GHD under 3 years old, but has no diagnostic significance for children with short stature above 3 years old.
The process of GHD diagnosis also requires evaluation of hypothalamic-pituitary-other endocrine axis function. Traumatic brain injury and aneurysmal subarachnoid hemorrhage can lead to temporary growth hormone deficiency and should be tested for growth hormone secretion status 12 months later. For children with diagnosed GHD, pituitary MRI should be performed to clarify whether the GHD is organic or not.
Idiopathic short stature
ISS refers to short stature that is lower than 2 standard deviations of the average height of normal children of the same sex and age; it excludes short stature caused by GHD, small for gestational age, systemic diseases, other endocrine diseases, nutritional diseases, chromosomal abnormalities, skeletal dysplasia, and psycho-emotional disorders. In essence, it is an umbrella term for a group of diseases with unknown etiology that cause short stature. 60% to 80% of children with short stature below -2s in height meet the definition of ISS, and the definition includes somatic pubertal growth retardation and familial short stature. Therefore, ISS is an exclusive diagnosis, and it is important to exclude other causes of short stature based on the patient’s medical history, family history, clinical presentation, physical examination, and relevant laboratory tests during the diagnosis process. At present, patients diagnosed with ISS may have reduced GH secretion, SHOX gene defect, GH promoter dysfunction, GH molecular abnormality, GH signaling pathway genetic defect, etc. With the widespread clinical application of genetic analysis techniques, more GH-IGF1 axis-related genetic abnormalities may be identified in children with ISS.
The treatment criteria for ISS are based on growth indicators, and there are no biochemical indicators to determine whether to initiate ISS treatment. height indications for ISS treatment vary depending on the country/region and clinical parameters. The United States and others specify the treatment criteria for ISS: -2.25s (<1.2 percentile) below the mean height of a normal healthy population of the same sex and age; the growth hormone research society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society of Endocrinology recommend -2 to -3 SDS below the mean height, and the recommended age for starting treatment is 5 years to early adolescence. Most of the foreign data of ISS patients rhGH treatment you say the age of 3~4 years old or more.
Domestic recommended treatment with rhGH for children with ISS should meet the following conditions: ① height lags behind the average height of normal healthy children of the same age and sex -2s; ② length and weight at birth are in the normal range for children of the same gestational age; ③ systemic diseases, other endocrine diseases, nutritional diseases, chromosomal abnormalities, skeletal dysplasia, psycho-emotional disorders and other causes of short stature are ruled out. ④ GH peak in GH drug provocation test ≥ 10ug/L; ⑤ The age of starting treatment is 5 years.
III. Children younger than fetal age
At present, there is no unified diagnostic criteria for children younger than gestational age at home and abroad. Different countries or regions have different diagnostic criteria. Most of them consider that a small-for-gestational-age infant is a newborn with birth weight and/or length below the 10th percentile of normal reference values for the same gestational age; or a newborn with birth weight below -2 standard deviations or the 3rd percentile of normal reference values for the same gestational age. The former is commonly used in China as a diagnostic indicator for infants younger than gestational age.
The FDA approved the use of rhGH for the treatment of small for gestational age infants in 2001, but not all children diagnosed as small for gestational age at birth need to be treated with rhGH. The majority of children younger than gestational age achieve catch-up growth between 6 and 12 months of age, and 90% of children younger than gestational age achieve catch-up growth by 2 to 3 years of age. However, it may take 4 or more years for preterm small for gestational age children to reach normal height range. Achieving catch-up growth includes two meanings: (1) length and weight exceed the 2s of normal children of the same age and sex; (2) growth rate exceeds the average value of children of the same age and gestational age. If the growth rate exceeds the average value for children of the same age and gestational age, then the growth rate fails to catch up.
Domestic and international experts do not agree on the age of initiation of treatment for children younger than fetal age. The US FDA recommends starting rhGH treatment in children younger than 2 years of age who have not achieved catch-up growth. The European EMEA recommends rhGH therapy for children over 4 years of age with a height SDS <-2.5; a growth rate lower than the mean for the same age; and a height SDS lower than 1 SD of the genetic target height SDS. The International Society for Pediatric Endocrinology and the GH Research Society recommend starting rhGH therapy for younger children aged 2 to 4 years without catch-up growth and with height SDS <-2.5; for younger children aged 4 years or older without catch-up growth and with height SDS of -2 to -2.5, there is no unified consensus on whether rhGH therapy should be used, but most experts believe that height <-2.0 SDS can be considered for rhGH therapy. rhGH treatment.
Domestic recommendations for rhGH treatment in children younger than gestational age include: ① birth weight and/or length lower than the 10th percentile of normal reference values for the same gestational age and sex; ② height ≥ 4 years of age still lower than the average height of children of the same age and sex – 2S.
The need to evaluate GH secretion status before rhGH treatment in children younger than gestational age is controversial. The GH-IGF1 axis in children younger than gestational age is variable, and typical GHD is rare. Some children may have a reduced 24-h GH secretion rate and lower levels of IGF1 and IGFBP3 than normal children and children of gestational age with short stature. If the growth rate continues to decrease in children younger than gestational age and they show signs of GH deficiency or hypopituitarism, the function of the GH-IFG1 axis should be evaluated and other pituitary endocrine axis functions should be evaluated if necessary.
Epidemiological data suggest that children younger than gestational age are at increased risk of cardiovascular disease, metabolic syndrome, and stroke in adulthood. rhGH treatment may be preceded by glucose metabolism function testing to rule out combined glucose metabolism abnormalities, depending on the child’s condition.
Turner syndrome
Turner syndrome is a common clinical sex chromosome abnormality with a prevalence of 1/2000~1/2500 live births in female infants. At the age of 1.5 years, 50% of Turner syndrome is less than the 5th percentile height; at the age of 3.5 years, 75% of Turner syndrome is less than the 5th percentile height; the chimeric Turner syndrome has different growth lag, but at the age of 2 years, 50% of Turner syndrome is still less than the 5th percentile height. However, at 2 years of age, 50% of Turner syndrome cases were still less than the 5th percentile height. In adults with Turner syndrome, height is about 20 cm shorter than the normal average, and the final adult height of untreated children with typical Turner syndrome is about 135-140 cm.
The diagnosis of typical Turner syndrome is based on: (1) growth retardation; (2) hypogonadism; (3) special physical features, such as low posterior hairline, facial nevus, neck webbing, elbow valgus, wide breast spacing, shield-shaped chest, short 4th and 5th metacarpal bones, etc.; and (4) karyotype analysis indicating complete deletion of X chromosome or structural abnormalities.
The mechanism of growth retardation in children with Turner syndrome is unknown, and the functional performance of the GH-IGF1 axis varies, so the results of GH stimulation test in children can be normal or GH partial deficiency can occur. Therefore, GH stimulation tests are not routinely performed, but for children whose growth rate deviates significantly from the Turner growth curve, attention should still be paid to the functional examination of the hypothalamic-pituitary axis. SHOX gene defects are relatively common in children with certain skeletal features of Turner syndrome, and SHOX gene analysis can be performed if necessary. It is generally accepted that GH therapy should be started when the height of a child with Turner syndrome is below the 5th percentile of the normal female growth curve, which may be as early as 2 years of age.
The karyotypes of children with Turner syndrome are complex and may include X monosomy, chimeric, X chromosome with broken or long arm deletion, X chromosome with long or short arm equivalence, ring X chromosome, and marker chromosome. If Turner syndrome is highly suspected clinically, but no abnormality is found by karyotype analysis of peripheral blood, it is necessary to perform skin fibroblast culture to exclude chimerism.
In recent years, molecular genetic studies have revealed that some children with Turner syndrome may have Y chromosome or fragments derived from Y chromosome, and the risk of gonadal malignancy increases by 30% in children with this karyotype, and the risk increases significantly with age. The prevalence of gonadal tumors is 3% at 10 years, 20% at 15 years, and 75% at 25 years, of which 2/3 are gonadoblastomas and 10% are more malignant endodermal sinus tumors or embryonal carcinomas. The treatment of rhGH in children with this karyotype should be very cautious.
V. Prader-Willi syndrome
Prader-Willi syndrome is a syndrome caused by paternal deletion of 15q11-13, maternal uniparental diploidy or abnormal imprinted genes such as sNRPN, NDN, MAGEL2 and MKRN3. The main clinical manifestations are feeding difficulties and hypotonia in infancy, growth retardation in early childhood, obesity, impaired intellectual development, and hypogonadotropic hypogonadism.
The mechanism of growth retardation in children with Prader-Willi syndrome is unknown, and some children may have GH deficiency, reduced IGF1 levels and decreased 24hGH secretion. levels before treatment to help evaluate the compliance and sensitivity of treatment. There is no consensus on the age of onset of treatment for Prader-Willi syndrome, but it is generally accepted that it is beneficial to start rhGH treatment before the onset of obesity (usually around 2 years of age). rhGH treatment can have significant effects on improving growth, body composition, and fat utilization in children with Prader-Willi syndrome. However, a combination of diet control and lifestyle interventions should be emphasized along with rhGH therapy.
Children with Prader-Willi syndrome are prone to tonsillar hypertrophy, adenoid hypertrophy, and upper airway obstruction, and children with severe obesity may suffer from severe respiratory dysfunction that may lead to death. Before rhGH treatment, special attention should be paid to examining the oropharynx, monitoring respiratory sleep and other related tests.
rhGH treatment does not increase the risk of insulin resistance in children, but children who are particularly obese or who gain weight rapidly are at increased risk of developing diabetes mellitus.
Severe obesity, uncontrolled diabetes mellitus, uncontrolled severe obstructive sleep apnea, active tumors, and active psychiatric disorders prohibit rhGH.
VI. Noonan syndrome
Noonan syndrome is a relatively common, multiple congenital malformations syndrome. The prevalence abroad is 1/1000~1/2500 live births, with equal incidence in both sexes. The main clinical manifestations are growth retardation, specific facial features, skeletal malformations, and congenital heart disease. 80% of Noonan syndrome is associated with congenital heart disease, mainly right heart system pathology, such as pulmonary stenosis and hypertrophic cardiomyopathy. The karyotype analysis of the affected children is normal. Genetic abnormalities involving PTPN11, KRAS, NRAS, SOS1, RAF1, BRAF, SHOC2, etc. have been reported.
Children with Noonan syndrome are born with normal length and weight. The function of GH-IGF1 axis in children with Noonan syndrome is reported to be variable, with 37%-45% of children showing growth hormone deficiency, and some children showing neurosecretory dysfunction or normal growth hormone secretion. The mechanism of growth failure in Noonan syndrome is unknown and may be related to the negative regulation of the GHR-JAK2-STAT5 signaling pathway by SHP2, and it has also been suggested that functionally acquired mutations in PTPN11 can cause partial insensitivity of growth hormone at post-receptor levels.
Ventricular hypertrophy, hypertrophic cardiomyopathy, and arrhythmias have been reported in children with Noonan syndrome treated with rhGH. Therefore, cardiac ultrasound and electrocardiogram should be noted before and during rhGH treatment.
VII. Other
In addition, some clinical data show that rhGH treatment can improve the growth of children with central precocious puberty, congenital adrenocortical hyperplasia, and congenital hypothyroidism after treatment of the original disease, and patients with significantly impaired predicted adult height (<160cm in boys and <150cm in girls).