Growth hormone deficiency in children

Introduction to pediatric growth hormone deficiency The short stature caused by the lack of growth hormone (GH), called growth hormone deficiency, also known as pituitary dwarfism, short stature refers to children in a similar environment, the height is lower than the same race, The same age, the same height of individuals with normal height of more than 2 standard deviations, or lower than the normal child growth curve 3rd percentile. Among many factors, endocrine growth hormone (GH) plays an important role in height. basic knowledge The proportion of illness: 0.0025% Susceptible people: children Mode of infection: non-infectious Complications: headache, hypoglycemia, craniopharyngioma

Causes of growth hormone deficiency in children

(1) Causes of the disease

The hypothalamus secretes GHRH and SS, promotes and regulates the secretion of GH from the pituitary, and further promotes the synthesis of IGF-1 and IGFBP-3 to act on the target organ, promoting growth and metabolism. The axis is called the growth axis, and the hypothalamus receives the advanced central nervous system. The incoming information is affected by it, and any obstacles in the growth axis can cause growth retardation and short stature.

1. Classification of causes of growth axis dysfunction

(1) hypothalamic-pituitary congenital anomaly: due to abnormal development of the central nervous system, hypothalamic-pituitary dysplasia leads to growth hormone deficiency, such as lack of whole brain or no brain, brain splitting, dysplasia, optic nerve development Poor, facial deformities such as single incisor midline dysplasia, optic nerve with hyaline septal dysplasia, cleft lip and palate and other congenital dysplasia, accompanied by hypothalamic defects and/or pituitary GH or a variety of pituitary hormone secretion Simple pituitary dysplasia is not associated with brain developmental disorders. It has been reported that siblings and cousins are sick, are autosomal recessive inheritance, empty sella, and the lack of sphenoidal septum causes the saddle membrane of the saddle to penetrate the saddle membrane. Deformation of the sella, flattening of the pituitary, and all congenital lesions of the central nervous system affecting the hypothalamus and pituitary tissue, most of the children may produce hypothalamic-pituitary-IGF-1 growth axis dysfunction leading to short, or lower Thalamic-pituitary secretion of various hormones.

(2) Destructive lesions: skull base fracture or hemorrhage, other injuries include hypoxic ischemic encephalopathy at birth, intracranial tumors, especially craniopharyngioma, glioma; meningitis, intracranial tuberculosis, toxoplasma Disease, granulomatosis, intracranial hemangioma, etc., for brain, eye and middle ear radiation therapy, such as central nervous system malignant tumors and cranial radiotherapy during leukemia treatment, can affect the growth of hormones in the growth axis, radiation therapy begins Age, single dose, total dose and time of each radiotherapy interval have different effects on the hypothalamus-pituitary. The younger age is more harmful than the older one, and the total dose of the hypothalamic-pituitary is >1800~ At 2000cGy, the incidence of GH axis disorder was higher and the start time was earlier. The dose <1800cGy could change the spontaneous secretion of GH in puberty. When the dose was >2400cGy, the spontaneous secretion of GH decreased, and the response could still be normal after stimulation. The dose was >2700cGy. Both spontaneous secretion and stimulation are affected. For example, in a short period of time, large doses of radiation therapy are more likely to cause GH axis deficiency. Generally, radiotherapy is often combined with chemotherapy, chemotherapy for intracranial or spinal cord. Injection is also in part due to growth failure.

(3) idiopathic growth hormone deficiency (IGHD): most patients with hypothalamic-pituitary function reduction can not find obvious lesions, such problems are mostly in the hypothalamus, often scattered, some For the birth of the breech and birth suffocation, or birth control, such as birth control, resulting in ischemia and hypoxia after birth.

(4) hereditary hypothalamic-pituitary-growth axis dysfunction: hereditary short stature can be used for a variety of reasons, McKusick has been classified as type I for autosomal recessive inheritance, type II autosomal dominant inheritance, type III linkage Genetic, previously attributed to idiopathic growth hormone deficiency (IGHD).

The GHRH-GH-IGF-1 axis gene defect is defective in GH1 (GH-N) gene, which is a gene producing hGH, which may have a complete deletion of the gene, a partial deletion or a fragment of a different size, or even a deletion of 1 to 2 bp. GH1 is completely deficient in IGHD1A type. A pair of sister GH deficiency has been reported in China. It is confirmed that the GH1 gene is completely deficient, and the autosomal recessive inheritance is IGHD1B type. It is a heterozygous GH1 gene with severe defects and point mutations, and the clinical GH is completely lacking. , autosomal dominant inheritance is a point mutation of GH1 gene, and mutation of one base of the third intron can cause GH mRNA to cleave the third exon, so that the synthesized GH lacks amino acids 32 to 71, lacking a cysteine. Alanine does not form intramolecular disulfide bonds, affecting the release of GH from secretory granules. X-linked IGHD type III is a familial GHD with immunoglobulin deficiency and may involve several linked gene deletions.

Hereditary multiple pituitary hormone deficiency is mostly autosomal recessive or sexually linked inheritance, with GH, TSH, ACTH, LH and FSH deficiency, while PRL is more normal or elevated, if the release factor of various hormones is administered to test the pituitary It can respond, indicating that the lesion is in the hypothalamus. Some families have a defect in the transcription factor Pit-1 gene. The Pit-1 gene is a transcription factor for GH, PRL and -TSH genes. This gene mutation causes GH, PRL and TSH is reduced, GHD is accompanied by a decrease in thyroid function, and GHD caused by a defect in the GHRH receptor gene is also found.

Growth hormone receptor gene deficiency is called GH insensitivity (GHI): GH receptor cannot be bound by GH receptor gene deletion or mutation, and GH cannot bind to it. The effect, so called GH is not sensitive, Laron syndrome is the first to be discovered due to the lack of congenital GH receptor, clinical hypoglycemia often occurs, growth disorders are similar to GHD, blood GH concentration is increased, and IGF-1 Very low, experimental studies have found that blood GH banding protein (GHBP) and nuclides labeled GH binding ability decreased, GHBP is the extracellular part of GH receptor, indicating GH receptor defective, exogenous GH No reaction, can not promote growth, the majority of children with Laron syndrome parents are in the normal range, this disease can be treated with IGF-1, and GH receptor gene point mutations, mostly occur in the extracellular region of the receptor structure, have been found Some can produce receptors but can not form dimers, in addition to abnormalities in post-receptor information transmission, secondary GHD can be caused by GH antibodies or GH receptor antibodies, malnutrition or liver disease, although blood GH is normal IGF-1 production Reduction also produces GHD, all growth hormone insensitivity, the basal values of GH in blood are normal or higher than normal, the concentration of IGF-1, IGF-II and IGFBP-3 in blood is reduced, in addition, some people will all cause GH Both deficiency and GH insensitivity are attributed to the IGF-1 deficiency class.

(5) Psychic growth disorder: once known as deprivational dwarf, due to environmental factors through the central nervous system to produce depression, affecting the secretion of hypothalamic-pituitary growth hormone, resulting in slower growth, if you can change the environment, mood Shu Chang, GH secretion can return to normal, and growth will also improve.

2. Classification of causes According to hypothalamic-GH-IGF axis functional defects, can be divided into:

(1) Primary:

1 Genetics: GH or GHRH gene abnormalities or receptor abnormalities.

2 idiopathic: hypothalamic dysfunction, a defect in the neurotransmitter-neurohormonal functional pathway.

3 dysplasia: pituitary is not developed, dysplasia, empty sella, depending on the septal hypoplasia.

(2) Secondary:

1 tumor: craniopharyngioma, neurofibroma, hamartoma, etc.

2 radiation damage: after radiotherapy.

3 head trauma: birth injury, surgical injury, skull base fracture and so on.

(3) IGF1 deficiency: IGF1 synthesis defect, IGF1 receptor defect, and the like.

(two) pathogenesis

1. Growth hormone and inferior colliculus-GH-IGF axis

(1) Growth hormone (GH) gene: GH is secreted by eosinophils in the anterior pituitary gland, contains 191 amino acids, is a non-glycosylated protein hormone, GH has a half-life of 15 to 30 min, and the human GH gene cluster consists of It consists of 5 members, located in the q22~24 region of the long arm of chromosome 17, and the order of the 5 genes is from 5' to 3' in order of hGH-N-hCS-L-hCS-A-hGH-V-hCS -B-3', the five gene DNA sequences are highly homologous, each gene contains 5 exons and 4 introns, of which hGH-N gene is expressed in the anterior pituitary eosinophils, The growth hormone is secreted, and the other four genes are expressed in placental trophoblast cells, which are related to placental development and fetal growth.

(2) GH secretion and regulation: within 3 months of gestational age, there is no GH secretion in the pituitary, and then the GH level in the blood gradually increases; by 12 weeks, the GH blood concentration can reach 60 g / L, reaching 30 g / L at 30 weeks After that, the GH concentration gradually decreased, and it was 30 g/L at birth, and then decreased further. The GH secretion was generally pulsed, and the fluctuation of day and night was large. When the low peak was secreted, it was often difficult to measure, and the blood concentration was often <5 g/L. The GH secretion was the most vigorous after sleeping for about 1 hour. In the later sleep, the lower peak was observed, and the normal peak rhythm of 24h was 6-8 times.

(3) Physiological effects of GH: GH has a wide range of physiological effects, both promoting growth and regulating metabolism. Its main functions are:

1 promote bone growth;

2 promote protein synthesis;

3 promote fat degradation;

4 reduce the use of glucose by peripheral tissues;

5 promote water, mineral metabolism;

6 also anti-aging, promote brain function, enhance myocardial function, improve immune function.

(4) Insulin-like growth factor (IGF-1): IGF-1 is a polypeptide produced by the liver in response to GH. It consists of 70 amino acids. The gene is located on the long arm of chromosome 12 and contains 6 exons. 90% of IGF-1 in the blood is synthesized by the liver, and the rest is synthesized by cells such as fibroblasts and collagen. The physiological role of IGF-1 is mainly to stimulate the proliferation, differentiation and collagen synthesis of chondrocytes, and IGF-1 synthesized by the liver. The blood binds to insulin-like growth factor binding protein (IGFBPs) and is transported to peripheral tissues to function. Chondrocytes, fibroblasts, muscle cells, and vascular endothelial cells all have IGF receptors.

(5) Hypothalamic-GH-IGF axis: Hypothalamic-GH-IGF axis is the main endocrine system regulating human growth, GH synthesis and secretion by hypothalamic growth hormone releasing hormone (GHRH) and growth hormone releasing inhibitory hormone (SS) Double control, in addition to promoting the secretion of GH, GHRH also increases intracellular mRNA, promotes GH synthesis, GHRH is also pulsed secretion, the mechanism is more complex, may be mainly regulated by a variety of neurotransmitters and neuropeptides of the central nervous system, Animal experiments confirmed the presence of GHRH receptors in the pituitary gland. GHRH and SS together regulate the release of GH. SS consists of 14 amino acids, which inhibit the production of GHRH. Both bind to the anterior pituitary-specific receptors, and their secretion is also affected by the central nervous system. The regulation of various neurotransmitters and neuropeptides in the nervous system, GH secretion is affected by stress, hypoglycemia, exercise, and promotes its secretion, endocrine hormones such as estrogen, testosterone, thyroxine also promote its secretion, and high blood sugar Free fatty acids inhibit the secretion of GH.

Growth hormone releasing peptides (GHRPs) are GH-promoting peptides that have been discovered in recent years and can be artificially synthesized. They stimulate the release of GH from pituitary gland by a different mode of action than GHRH. GHRP-6 is the first GHRP to be discovered, and its derivatives are Hexarelin, intravenous injection can promote GH secretion, and some research reports have been published.

2. Growth disorders related gene growth is an extremely complex process that requires regulation of gene expression and cell division and proliferation. Human growth and final height are affected by genetic factors, congenital factors, birth weight and height, nutrition and hormones, etc. Factors play a role, with the development of endocrine molecular biology, in recent years, some genes that cause dwarf genes, leading to growth disorders and gene mutations, have been discovered.

Prevention of growth hormone deficiency in children

Primary growth hormone deficiency, most patients have unknown causes, only a small part of the family history, is autosomal recessive; secondary growth hormone deficiency is rare, any lesions can damage the anterior pituitary or hypothalamus Cause growth and development stagnation, common tumors (such as craniopharyngioma, chiasm or hypothalamic glioma, pituitary xanthoma, etc.), infection (such as encephalitis, tuberculosis, schistosomiasis, toxoplasmosis, etc.), Trauma, vascular necrosis and X-ray injury, etc., it is very important to prevent various infections, prevent central nervous system damage, and do a good job in counseling and prevention of hereditary diseases.

Pediatric growth hormone deficiency complications Complications, headache, hypoglycemia, craniopharyngioma

When the hypothalamus or pituitary is severely damaged, multiple pituitary gonadotropins may occur. In addition to GH deficiency, there may be TSH, ACTH and/or gonadotropin LH, FSH deficiency, causing hypothyroidism, adrenal atrophy, and sexual organs. Developmental disorders, increased incidence of hypoglycemia, more common intracranial masses are craniopharyngioma or saddle and saddle masses, which can be followed by growth and backwardness, followed by increased intracranial pressure, headache, vomiting, vision Obstacles and fundus changes, and some symptoms appear after craniocerebral surgery.

Symptoms of growth hormone deficiency in children Common symptoms Hypothyroidism Slow growth Slow development of urine collapse Multi-urinary bone delay Delayed polydipsia Delayed amenorrhea

Children with growth hormone deficiency, especially those without congenital head malformation, have normal body length and body weight at birth, while children with GH insensitivity or GH receptor deficiency can be born less than normal, and severe GH deficiency such as GHD The gene is missing and can be significantly shorter than the normal mean -4SD at 1 year of age.

Some children with GH deficiency have a history of dystocia at birth, a history of asphyxia or a misplaced position. The breech position is more common in the foot position. The body length is normal at birth. The growth slows down from 5 months after birth, and is obviously 1 to 2 years old. More attention is paid after more than 2 to 3 years old. As the age increases, the degree of slow growth increases. The body shape is younger than the actual age. The proportion of limbs and body is well-proportioned. The appetite is low since childhood, and the typical one is short and the subcutaneous fat is relatively high. Abdominal fat accumulation, round face, slightly protruding forehead, small lower jaw, normal upper and lower parts, well-balanced limbs, high-pitched sound, annual growth rate of school-age height less than 4cm, severely only 2~3cm, height deviation in normal mean-2SD Below, the child has normal intelligence, teething, tooth replacement and bone age are delayed.

Most of the puberty is delayed, accompanied by other gonadotropins in the pituitary gland, mostly lacking gonadotrophic hormone, showing no sexual development, boy's small penis, small testicles, girls' breasts are not developed, primary amenorrhea; Absence of ACTH often results in skin pigmentation and severe hypoglycemia; accompanied by thyroid-stimulating hormone deficiency, it is characterized by hypothyroidism, and some cases are accompanied by polydipsia and partial diabetes insipidus.

Examination of pediatric growth hormone deficiency

1. Determination of blood GH: serum GH value is low, pulse-type secretion, short half-life, random blood sampling often can not distinguish between normal people and GH deficiency, so one-time specimen determination is meaningless, clinically often used drug stimulation test For diagnosis, it is necessary to fast for 8 hours before the test, but it is not necessary to ban water. If GH peak is <5g/L, it is complete GH deficiency; GH peak is 5.19.9g/L for partial GH deficiency; GH peak 10g /L is a normal reaction.

2. IGF-1 assay: GH mediates the growth effect of IGF-1 and is another important indicator reflecting the function of GH-IGF-cartilage axis. IGF concentration is related to age and is also affected by thyroxine, prolactin, cortisol and The influence of nutritional status, IGF-1 determination has certain differential diagnosis significance, such as the increase of GH in short children, and the low IGF-1 value, should be considered to have resistance to GH.

3. Insulin-like growth factor binding protein 3 (IGFBP3) assay: 95% of IGF-1 in circulating blood binds to IGFBP3, binds with high affinity and specificity, and can regulate the effect of IGF-1 on cell proliferation, metabolism and mitosis. .

4. Chromosome examination: For women with short stature and puberty development delay, routine chromosomal examination should be performed to exclude chromosomal diseases such as Tumer syndrome.

5. X-ray film: Height growth depends mainly on the changes of the long bones. The bone age of GH deficiency is delayed, generally more than -2SD. In addition, the head can be photographed, the lateral position, the size of the saddle and the skull, cranial suture Wait for changes.

6. Brain magnetic resonance imaging (MRI): MRI can clearly show the size of the saddle, the size of the anterior pituitary and posterior lobes, can diagnose the pituitary dysplasia, dysplasia, empty sella, visual septal hypoplasia, etc. Found tumors such as craniopharyngioma, neurofibromatosis, hamartoma.

Diagnosis and differential diagnosis of growth hormone deficiency in children

Typical growth hormone deficiency should meet the following:

1. The height is the same as the same age, and the average gender is lower than -2SD.

2. The annual growth rate of height is <4cm. The growth rate of young children is less than 2/3 of normal.

3. The body is well-proportioned, the face is childish, the subcutaneous fat is fuller, and some children have more facial paralysis. Some children may be accompanied by diabetes insipidus or other pituitary hormone deficiency.

4. Both drugs were tested for GH challenge, and the peak GH was <10 g/L.

5. Excluding hypothyroidism, chronic liver, kidney disease and skeletal system diseases.

6. The bone age is 2 years older than the actual age.

7. Skull magnetic resonance shows a reduction in pituitary gland.

Growth hormone deficiency needs to be identified with the following diseases:

1. Intrauterine growth retardation: Usually the full-term infants with less than 2.5kg are diagnosed as intrauterine growth retardation (IUGR). At present, the disease can be divided into two categories: one is the common type of IUGR, the performance The symmetry is short, the other is asymmetrical short stature (Russell-Silver syndrome), the endocrine function test is generally normal, no growth hormone deficiency.

The common type of IUGR has no gender difference, except for the shortness of the symmetry, and it is not accompanied by malformation. It shows weight loss, slenderness, abdominal fat accumulation; general appetite, triangular face, small mandible, wide forehead, abnormal sexual development, and bone age are often delayed.

Both men and women may have Russell-Silver sign, in addition to low birth weight and small size, often accompanied by a variety of malformations or developmental abnormalities, such as:

(1) Unilateral limb hypertrophy.

(2) high amount, wide eye distance, sagging angle, skin hemangioma, etc.

(3) craniofacial bone development abnormalities, small face, triangular face, can also have a fifth finger short bending, and toe.

(4) Individuals have mental retardation and low intelligence.

(5) may be associated with abnormal renal function, hypospadias, skin pigmentation, hypoglycemia, Wilms tumor.

2. Physique growth and development delay: constitutional growth and developmental puberty is more common in boys, accounting for more than 1/3 of children with short stature, parents may have delayed puberty development History, the more obvious sexual development delay, the more common family history, the endocrine function test is generally normal, but the GH level can be partially or temporarily deficient after drug stimulation, but delayed spontaneous development of puberty It is still possible to bring its lifelong high and sexual maturity to a normal level, so this kind of child is a variation in normal growth and development.

3. Idiopathic short stature: idiopathic short stature needs to rule out all known causes, no organic disease, the child is born at height, normal weight, short and well-proportioned, its natural secretion of GH (physiological secretion) ) and the peak after drug stimulation is within the normal range, usually short and not serious, can be at -2.2 (±0.6) SD level, the growth rate of height can be similar to normal children or slightly slow, other endocrine hormones and biochemical indicators are not Significant changes, no puberty development delay, in recent years, people have tried GH treatment, that the recent height growth is slightly accelerated, but life-long high can not reach the standard, so the family-like dwarf without normal GH deficiency, whether it is necessary to use long-range expensive GH drug treatment is still controversial.

4. Nutritional deficiency: The most important cause of nutritional growth retardation or nutritional shortness is insufficient nutrition due to poverty, but it is also seen in the subjective self-limiting diet, the intake of nutrients is unreasonable and the growth is affected. Although the weight of the child is lower than that of the same age, the weight/height ratio is often similar to that of the non-nutritional short (familial short, short stature), so it is difficult to distinguish, organic disease or non-organic diseases. Can lead to nutritional deficiencies, growth retardation is temporary, restoring adequate nutrient intake and adjusting the diet to make it reasonable, growth can be accelerated.

5. Mental and psychological disorders: Psychosocial short stature often occurs when there are parents' disagreements, divorced families or single-parent families, children's mental and psychological frustration affects the hypothalamus-GH-IGF Axis function, GH secretion can be normal or lacking, the mechanism of this disease is complex, may be related to chronic nutritional deficiency and GH neurosecretory dysfunction.

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