The diagnosis and treatment of growth hormone deficiency in children and adolescents is a widely debated topic. In order to enable patients to be properly identified and treated, the Growth Hormone Research Society (GRS) convened a symposium in Eilat, Israel, October 17-21, 1999, on the topic of establishing a universally accepted treatment and diagnostic principle for growth hormone deficiency (GHD) in children and adolescents. The GRS invited leading clinical and scientific experts in this field, including many medical and health authorities from synthetic GH manufacturing companies, to work together to complete this principle, as detailed below.
I. Diagnosis of GHD in children.
The diagnosis of GHD in children is a multifaceted process that requires a combination of clinical and developmental evaluation, along with measurement of insulin-like growth factors and radiological assessment. GHD may manifest as a single GH deficiency or may be associated with multiple pituitary hormone deficiencies (MPHD). Each component of this process requires discriminatory criteria, which are presented as follows.
1. Clinical and developmental criteria.
The evaluation of GHD in children with short stature below 2 SD should first exclude hypothyroidism, chronic systemic systemic diseases, Turner’s syndrome or skeletal disorders (skeletal disorder),The key factors that indicate the possible occurrence of GHD in the history and physical examination are
(1) Neonatal period: hypoglycemia, delayed yellow bile, small penis. (2) History of intracranial irradiation. (3) History of brain injury or central nervous system infection. (4) Family history of close relatives or number of affected family members. (5) Craniofacial midline abnormalities.
It is recognized that short stature is often the only sign of GHD, and the criteria include: 1) severe short stature, more than 3 SD below standard height (below the mean); 2) more than 1.5 SD below the median height of both parents; 3) more than 2 SD below standard height and a growth rate 1 SD below normal for the same age, or an annual decrease in growth rate of 0.5 SD in children older than 2 years. 0.5 SD. 4) In addition to short stature, a growth rate below the mean of 2 SD at 1 year of age or more than 1.5 SD above 2 years of age, these occur in GHD and can persist in infancy or in organically acquired GHD; show symptoms of intracranial damage; 6) symptoms of MPHD; 7) symptoms of neonatal period and physical evidence of GHD.
It is important to note that growth data should be interpreted using the most recent population growth criterion, which, when possible, should be adjusted to the developmental tendencies of the population over time, generally updated every 10-20 y. Growth data are expressed as SD rather than percentages. Longitudinal comparison of rate change criteria is necessary to properly assess the rate of height growth. in vitro biological markers of GH-IGF, while body composition, bone mineral density and bone markers, are no longer relevant for the diagnosis of GHD.
With the extensive use of MRI, abnormal signals are occasionally detected in the hypothalamic-pituitary region. These require clinical evaluation and possible growth monitoring of the child. Based on clinical considerations, ophthalmologic examination is also warranted.
2. Evaluation of genetic disorders
Genetic disorders producing GHD and MPHD have been increasingly identified and include these conditions: 1. early development of growth retardation; 2. positive family history and possible consanguinity; 3. height below standard 3 SD or more; 4. excitation tests showing very low GH responsiveness, including GHRH, very low IGF-1 and IGF binding protein -3 levels.
Genetic change testing is now limited to the laboratory research phase. It is very pleasing to see that these tests are becoming more widely used. By complying with ethical and legal considerations, a DNA bank should be established
3. Radiological evaluation
Determination of bone age by x-ray of the left wrist and finger radiographs is a very important part of the assessment of growth retardation in children over 1 year of age, and in infants under 1 year of age, it is useful to be able to determine bone age by x-ray of the knee and ankle joints.
Central nervous system imaging by MRI and CT is performed for those with known or suspected intracranial tumors, optic nerve hypoplasia/optic septal dysplasia, or other structural and developmental abnormalities. After determining that IGHD and MPHD are not related to genetic influences, the following MRI data should be recorded (preferably in 2-mm sections: pituitary height and volume, position of the pituitary stalk, and posterior pituitary lobe, etc.). However, the need for additional morphological data to improve the quality of the evaluation has been recognized. Resolution of hypothalamic a pituitary region was performed under CT scan, but later it was mostly used for tumors and skeletal abnormalities. Intracranial calcifications are often found in craniopharyngiomas.
4. Biochemical evaluation of GHD
Identification conditions, there are now a considerable number of assays such as GH, IGF-1 and IGFBP-3. To improve the standard, it is recommended that GH reference operation should be combined with 22-KDa of human GH.(3Iu = 1mg) (Referencd Preparation), recombinant technology IGF-1 is provided by WHO, and the method is clearly stated when reporting the assay results, clinical Worker should know the method of its determination, its upper limit when using any assay. Implementation of the diagnosis of GHD – the use of monoclonal antibodies for the determination of 22-KDGH can be recommended.
5. GH excitation test and IGF-I/IGFBP-3 assay.
A limited number of excitation reagents should be used after standardization on an empty stomach
including: arginine, colistin, insulin, glucagon and L-dopa. Such experiments must be performed under the supervision of experienced personnel and special care should be taken when insulin and glucagon are used in children.
Clinical criteria for children with GHD: peak GH <10ug/L, this value should be corrected when monoclonal antibodies are used.
6. Estrogen to fill test.
It is known that the diagnosis of GHD before and after puberty is more difficult, and the stimulation test often produces low GH levels.
7.Measurement of newborns
In the absence of metabolic disorders, GH levels are usually measured in neonates with hypoglycemia. If the GH level is below 20ug/L as determined by random polyclonal antibody, it indicates that the newborn is suffering from GHD, and IGFBP-3 measurement is valuable for the diagnosis of GHD in infants.
8.Other methods of GH axis measurement
Urinary GH, plasma IGF-II and IGFBP-2, as well as unstable acid subunit levels and pro-GH secretagogues (e.g. stimulants) are not considered as diagnostic tests, but in combination with other measurements, these data are valuable. Simultaneous measurement of G HRH and arginine can help in the diagnosis of GHD, and this test has a high degree of specificity. It can provide an appropriate cut-off value.
When there is a conflict between GH and IGF data, such as normal GH and low IGF-1, spontaneous 12 or 24 hour GH secretion can be measured, and GH neurosecretory insufficiency is also a GH secretion abnormality. In addition, the IGF-1/IGFBP-3 production test is not very effective in the diagnosis of GHD. However, it is not sensitive for the diagnosis of GH, i.e. GH resistance. The diagnosis of biologically inactive GH is useful.
9. Confounding factors
The GH-IGF axis is very important to distinguish from other factors affecting growth, such as nutritional status, application of drugs (e.g. glucocorticoids, neurological drugs, etc.). Clinicians should always pay attention to the warning signs that can indicate abnormalities in the GH-IGF axis.
10. The process of GH-IGF axis evaluation
When a child is developmentally delayed and the history and developmental studies suggest GHD, after excluding hypothyroidism, IGF/IGFBP-3 levels are measured and a GH provocation test is performed to determine whether there is a GH/IGF-1 deficiency. If simple GHD is suspected, 2 GH stimulation tests (continuous or over several days) are performed. If there is a clear CNS abnormality, history of radiation, MPHD or genetic defect, one GH assay is sufficient. In addition, other pituitary hormone evaluations are required. In patients with a history of cranial radiation exposure or hypothalamic-pituitary malformation, whose GHD may have been present for several years, its diagnosis may require a repeat test of the GH-IGF axis.
Although IGF-1 and/or IGFBP-3 levels are below the normal range in some patients with developmental suggestive of GHD, their GH response levels are above cut-off values in the provocation test. These children are generally not classified as GH deficient, but still have the possibility of GH/IGF axis abnormalities. They can be considered for GH treatment after ruling out that the synthesis and action of IGF-1 is affected due to a systemic disorder.
MR1 or CT scans of the brain should be taken in all children diagnosed with GHD, with special attention to the hypothalamic-pituitary region.
11. Conclusion
Severe GHD is usually straightforward to diagnose because of very clear and definite clinical, developmental, biochemical and radiological abnormalities. However, children with moderate GHD sometimes present with normal IGF axis values and normal MRI images, so it is very important to carefully verify the effects of GH therapy, especially for those with moderate degrees.
The diagnosis and treatment of growth hormone deficiency in children and adolescents is a widely debated topic, and in order to enable proper identification and treatment of patients, the Growth Hormone Research Society (GRS) convened a symposium in Eilat, Israel, October 17-21, 1999, on the topic of establishing a universally accepted treatment for growth hormone deficiency (GHD) in children and adolescents The GRS invited leading clinical and scientific experts in this field, including many authorities in health care from companies that manufacture synthetic GH, to work together to complete this principle, as detailed below.
II. GHD diagnosis in children.
The diagnosis of GHD in children is a multifaceted process that requires a combination of clinical and developmental evaluation, along with measurement of insulin-like growth factors and radiological assessment. GHD may manifest as a single GH deficiency or may be associated with multiple pituitary hormone deficiencies (MPHD). Each component of this process requires discriminatory criteria, which are presented as follows.
1. Clinical and developmental criteria.
The evaluation of GHD in children with short stature below 2 SD should first exclude hypothyroidism, chronic systemic systemic diseases, Turner’s syndrome or skeletal disorders (skeletal disorder),The key factors that indicate the possible occurrence of GHD in medical history and physical examination are
(1) Neonatal period: hypoglycemia, delayed yellow bile, small penis. (2) History of intracranial irradiation. (3) History of brain injury or central nervous system infection. (4) Family history of close relatives or number of affected family members. (5) Craniofacial midline abnormalities.
It is recognized that short stature is often the only sign of GHD, and the criteria include: 1) severe short stature, more than 3 SD below standard height (below the mean); 2) more than 1.5 SD below the median height of both parents; 3) more than 2 SD below standard height and a growth rate 1 SD below normal for the same age, or an annual decrease in growth rate of 0.5 SD in children older than 2 years. 0.5 SD. 4) In addition to short stature, a growth rate below the mean of 2 SD at 1 year of age or more than 1.5 SD above 2 years of age, these occur in GHD and can persist in infancy or in organically acquired GHD; show symptoms of intracranial damage; 6) symptoms of MPHD; 7) symptoms of neonatal period and physical evidence of GHD.
It is important to note that growth data should be interpreted using the most recent population growth criterion, which, when possible, should be adjusted to the developmental tendencies of the population over time, generally updated every 10-20 y. Growth data are expressed as SD rather than percentages. Longitudinal comparison of rate change criteria is necessary to properly assess the rate of height growth. in vitro biological markers of GH-IGF, while body composition, bone mineral density and bone markers, are no longer relevant for the diagnosis of GHD.
With the extensive use of MRI, abnormal signals are occasionally detected in the hypothalamic-pituitary region. These require clinical evaluation and possible growth monitoring of the child. Based on clinical considerations, ophthalmologic examination is also warranted.
2. Evaluation of genetic disorders
Genetic disorders producing GHD and MPHD have been increasingly identified and include these conditions: 1. early development of growth retardation; 2. positive family history and possible consanguinity; 3. height below standard 3 SD or more; 4. excitation tests showing very low GH responsiveness, including GHRH, very low IGF-1 and IGF binding protein -3 levels.
Genetic change testing is now limited to the laboratory research phase. It is very pleasing to see that these tests are becoming more widely used. By complying with ethical and legal considerations, a DNA bank should be established
3. Radiological evaluation
Determination of bone age by x-ray of the left wrist and finger radiographs is a very important part of the assessment of growth retardation in children over 1 year of age, and in infants under 1 year of age, it is useful to be able to determine bone age by x-ray of the knee and ankle joints.
Central nervous system imaging by MRI and CT is performed for those with known or suspected intracranial tumors, optic nerve hypoplasia/optic septal dysplasia, or other structural and developmental abnormalities. After determining that IGHD and MPHD are not related to genetic influences, the following MRI data should be recorded (preferably in 2-mm sections: pituitary height and volume, position of the pituitary stalk, and posterior pituitary lobe, etc.). However, the need for additional morphological data to improve the quality of the evaluation has been recognized. Resolution of hypothalamic a pituitary region was performed under CT scan, but later it was mostly used for tumors and skeletal abnormalities. Intracranial calcifications are often found in craniopharyngiomas.
4. Biochemical evaluation of GHD
Identification conditions, there are now a considerable number of assays such as GH, IGF-1 and IGFBP-3. To improve the standard, it is recommended that GH reference operation should be combined with 22-KDa of human GH.(3Iu = 1mg) (Referencd Preparation), recombinant technology IGF-1 is provided by WHO, and the method is clearly stated when reporting the assay results, clinical Worker should know the method of its determination, its upper limit when using any assay. Implementation of the diagnosis of GHD – the use of monoclonal antibodies for the determination of 22-KDGH can be recommended.
5. GH excitation test and IGF-I/IGFBP-3 assay.
A limited number of excitation reagents should be used after standardization on an empty stomach
including: arginine, colistin, insulin, glucagon and L-dopa. Such experiments must be performed under the supervision of experienced personnel and special care should be taken when insulin and glucagon are used in children.
Clinical criteria for children with GHD: peak GH <10ug/L, this value should be corrected when monoclonal antibodies are used.
6. Estrogen to fill test.
It is known that the diagnosis of GHD before and after puberty is more difficult, and the stimulation test often produces low GH levels.
7.Measurement of newborns
In the absence of metabolic disorders, GH levels are usually measured in neonates with hypoglycemia. If the GH level is below 20ug/L as determined by random polyclonal antibody, it indicates that the newborn is suffering from GHD, and IGFBP-3 measurement is valuable for the diagnosis of GHD in infants.
8.Other methods of GH axis measurement
Urinary GH, plasma IGF-II and IGFBP-2, as well as unstable acid subunit levels and pro-GH secretagogues (e.g. stimulants) are not considered as diagnostic tests, but in combination with other measurements, these data are valuable. Simultaneous measurement of G HRH and arginine can help in the diagnosis of GHD, and this test has a high degree of specificity. It can provide an appropriate cut-off value.
When there is a conflict between GH and IGF data, such as normal GH and low IGF-1, spontaneous 12 or 24 hour GH secretion can be measured, and GH neurosecretory insufficiency is also a GH secretion abnormality. In addition, the IGF-1/IGFBP-3 production test is not very effective in the diagnosis of GHD. However, it is not sensitive for the diagnosis of GH, i.e. GH resistance. The diagnosis of biologically inactive GH is useful.
9. Confounding factors
The GH-IGF axis is very important to distinguish from other factors affecting growth, such as nutritional status, application of drugs (e.g. glucocorticoids, neurological drugs, etc.). Clinicians should always pay attention to the warning signs that can indicate abnormalities in the GH-IGF axis.
10. The process of GH-IGF axis evaluation
When a child is developmentally delayed and the history and developmental studies suggest GHD, after excluding hypothyroidism, IGF/IGFBP-3 levels are measured and a GH provocation test is performed to determine whether there is a GH/IGF-1 deficiency. If simple GHD is suspected, 2 GH stimulation tests (continuous or over several days) are performed. If there is a clear CNS abnormality, history of radiation, MPHD or genetic defect, one GH assay is sufficient. In addition, other pituitary hormone evaluations are required. In patients with a history of cranial radiation exposure or hypothalamic-pituitary malformation, whose GHD may have been present for several years, its diagnosis may require a repeat test of the GH-IGF axis.
Although IGF-1 and/or IGFBP-3 levels are below the normal range in some patients with developmental suggestive of GHD, their GH response levels are above cut-off values in the provocation test. These children are generally not classified as GH deficient, but still have the possibility of GH/IGF axis abnormalities. They can be considered for GH treatment after ruling out that the synthesis and action of IGF-1 is affected due to a systemic disorder.
MR1 or CT scans of the brain should be taken in all children diagnosed with GHD, with special attention to the hypothalamic-pituitary region.
11. Conclusion
Severe GHD is usually straightforward to diagnose because of very clear and definite clinical, developmental, biochemical and radiological abnormalities. However, children with moderate GHD sometimes present with normal IGF axis values and normal MRI images, so it is very important to carefully verify the effects of GH therapy, especially for those with moderate degrees.
The diagnosis and treatment of growth hormone deficiency in children and adolescents is a widely debated topic, and in order to enable proper identification and treatment of patients, the Growth Hormone Research Society (GRS) convened a symposium in Eilat, Israel, October 17-21, 1999, on the topic of establishing a universally accepted treatment for growth hormone deficiency (GHD) in children and adolescents The GRS invited leading clinical and scientific experts in this field, including many authorities in health care from synthetic GH manufacturing companies, to work together to accomplish this principle, as detailed below.
III. GHD diagnosis in children.
The diagnosis of GHD in children is a multifaceted process that requires a combination of clinical and developmental evaluation, along with measurement of insulin-like growth factors and radiological assessment. GHD may manifest as a single GH deficiency or may be associated with multiple pituitary hormone deficiencies (MPHD). Each component of this process requires discriminatory criteria, which are presented as follows.
1. Clinical and developmental criteria.
The evaluation of GHD in children with short stature below 2 SD should first exclude hypothyroidism, chronic systemic systemic diseases, Turner’s syndrome or skeletal disorders (skeletal disorder),The key factors that indicate the possible occurrence of GHD in medical history and physical examination are
(1) Neonatal period: hypoglycemia, delayed yellow bile, small penis. (2) History of intracranial irradiation. (3) History of brain injury or central nervous system infection. (4) Family history of close relatives or number of affected family members. (5) Craniofacial midline abnormalities.
It is recognized that short stature is often the only sign of GHD, and the criteria include: 1) severe short stature, more than 3 SD below standard height (below the mean); 2) more than 1.5 SD below the median height of both parents; 3) more than 2 SD below standard height and a growth rate 1 SD below normal for the same age, or an annual decrease in growth rate of 0.5 SD in children older than 2 years. 0.5 SD. 4) In addition to short stature, a growth rate below the mean of 2 SD at 1 year of age or more than 1.5 SD above 2 years of age, these occur in GHD and can persist in infancy or in organically acquired GHD; show symptoms of intracranial damage; 6) symptoms of MPHD; 7) symptoms of neonatal period and physical evidence of GHD.
It is important to note that growth data should be interpreted using the most recent population growth criterion, which, when possible, should be adjusted to the developmental tendencies of the population over time, generally updated every 10-20 y. Growth data are expressed as SD rather than percentages. Longitudinal comparison of rate change criteria is necessary to properly assess the rate of height growth. in vitro biological markers of GH-IGF, while body composition, bone mineral density and bone markers, are no longer relevant for the diagnosis of GHD.
With the extensive use of MRI, abnormal signals are occasionally detected in the hypothalamic-pituitary region. These require clinical evaluation and possible growth monitoring of the child. Based on clinical considerations, ophthalmologic examination is also warranted.
2. Evaluation of genetic disorders
Genetic disorders producing GHD and MPHD have been increasingly identified and include these conditions: 1. early development of growth retardation; 2. positive family history and possible consanguinity; 3. height below standard 3 SD or more; 4. excitation tests showing very low GH responsiveness, including GHRH, very low IGF-1 and IGF binding protein -3 levels.
Genetic change testing is now limited to the laboratory research phase. It is very pleasing to see that these tests are becoming more widely used. By complying with ethical and legal considerations, a DNA bank should be established
3. Radiological evaluation
Determination of bone age by x-ray of the left wrist and finger radiographs is a very important part of the assessment of growth retardation in children over 1 year of age, and in infants under 1 year of age, it is useful to be able to determine bone age by x-ray of the knee and ankle joints.
Central nervous system imaging by MRI and CT is performed for those with known or suspected intracranial tumors, optic nerve hypoplasia/optic septal dysplasia, or other structural and developmental abnormalities. After determining that IGHD and MPHD are not related to genetic influences, the following MRI data should be recorded (preferably in 2-mm sections: pituitary height and volume, position of the pituitary stalk, and posterior pituitary lobe, etc.). However, the need for additional morphological data to improve the quality of the evaluation has been recognized. Resolution of hypothalamic a pituitary region was performed under CT scan, but later it was mostly used for tumors and skeletal abnormalities. Intracranial calcifications are often found in craniopharyngiomas.
4. Biochemical evaluation of GHD
Identification conditions, there are now a considerable number of assays such as GH, IGF-1 and IGFBP-3. To improve the standard, it is recommended that GH reference operation should be combined with 22-KDa of human GH.(3Iu = 1mg) (Referencd Preparation), recombinant technology IGF-1 is provided by WHO, and the method is clearly stated when reporting the assay results, clinical Worker should know the method of its determination, its upper limit when using any assay. Implementation of the diagnosis of GHD – the use of monoclonal antibodies for the determination of 22-KDGH can be recommended.
5. GH excitation test and IGF-I/IGFBP-3 assay.
A limited number of excitation reagents should be used after standardization on an empty stomach
including: arginine, colistin, insulin, glucagon and L-dopa. Such experiments must be performed under the supervision of experienced personnel and special care should be taken when insulin and glucagon are used in children.
Clinical criteria for children with GHD: peak GH <10ug/L, this value should be corrected when monoclonal antibodies are used.
6. Estrogen to fill test.
It is known that the diagnosis of GHD before and after puberty is more difficult, and the stimulation test often produces low GH levels.
7.Measurement of newborns
In the absence of metabolic disorders, GH levels are usually measured in neonates with hypoglycemia. If the GH level is below 20ug/L as determined by random polyclonal antibody, it indicates that the newborn is suffering from GHD, and IGFBP-3 measurement is valuable for the diagnosis of GHD in infants.
8.Other methods of GH axis measurement
Urinary GH, plasma IGF-II and IGFBP-2, as well as unstable acid subunit levels and pro-GH secretagogues (e.g. stimulants) are not considered as diagnostic tests, but in combination with other measurements, these data are valuable. Simultaneous measurement of G HRH and arginine can help in the diagnosis of GHD, and this test has a high degree of specificity. It can provide an appropriate cut-off value.
When there is a conflict between GH and IGF data, such as normal GH and low IGF-1, spontaneous 12 or 24 hour GH secretion can be measured, and GH neurosecretory insufficiency is also a GH secretion abnormality. In addition, the IGF-1/IGFBP-3 production test is not very effective in the diagnosis of GHD. However, it is not sensitive for the diagnosis of GH, i.e. GH resistance. The diagnosis of biologically inactive GH is useful.
9. Confounding factors
The GH-IGF axis is very important to distinguish from other factors affecting growth, such as nutritional status, application of drugs (e.g. glucocorticoids, neurological drugs, etc.). Clinicians should always pay attention to the warning signs that can indicate abnormalities in the GH-IGF axis.
10. The process of GH-IGF axis evaluation
When a child is developmentally delayed and the history and developmental studies suggest GHD, after excluding hypothyroidism, IGF/IGFBP-3 levels are measured and a GH provocation test is performed to determine whether there is a GH/IGF-1 deficiency. If simple GHD is suspected, 2 GH stimulation tests (continuous or over several days) are performed. If there is a clear CNS abnormality, history of radiation, MPHD or genetic defect, one GH assay is sufficient. In addition, other pituitary hormone evaluations are required. In patients with a history of cranial radiation exposure or hypothalamic-pituitary malformation, whose GHD may have been present for several years, its diagnosis may require a repeat test of the GH-IGF axis.
Although IGF-1 and/or IGFBP-3 levels are below the normal range in some patients with developmental suggestive of GHD, their GH response levels are above cut-off values in the provocation test. These children are generally not classified as GH deficient, but still have the possibility of GH/IGF axis abnormalities. They can be considered for GH treatment after ruling out that the synthesis and action of IGF-1 is affected due to a systemic disorder.
MR1 or CT scans of the brain should be taken in all children diagnosed with GHD, with special attention to the hypothalamic-pituitary region.
11. Conclusion
Severe GHD is usually straightforward to diagnose because of very clear and definite clinical, developmental, biochemical and radiological abnormalities. However, children with moderate GHD sometimes present with normal IGF axis values and normal MRI images, so it is very important to carefully verify the effects of GH treatment, especially for those patients with moderate