Growth hormone deficiency


Introduction to growth hormone deficiency

Children with growth and development disorders due to insufficient growth hormone secreted by the anterior pituitary gland, and short stature are called growth hormone deficiency. Common causes of insufficient growth hormone secretion in the anterior pituitary are: 1 primary: pituitary dysfunction 2 secondary: tumor, radiation injury, head trauma, intracranial infection, etc. any lesion damage the anterior pituitary or hypothalamus Can cause growth retardation. Sometimes the bad stimulation of the surrounding living environment can make children's mental trauma, and can also temporarily cause growth hormone deficiency.

basic knowledge

The proportion of sickness: 0.01% - 0.03%

Susceptible people: no special people

Mode of infection: non-infectious

Complications: developmental delay


Causes of growth hormone deficiency

(1) Causes of the disease

1. Idiopathic growth hormone deficiency

The majority of these patients are not well understood. The available data indicate that most of the idiopathic growth hormone deficiency causes lesions in the hypothalamus, and the release of growth hormone releasing hormone (GHRH) is significantly reduced. Some autopsy data found that there are enough growth hormone cells in the anterior pituitary and a considerable amount of intracellular growth hormone storage. These children respond well to treatment with GHRH and its analogues. GHRH can not only promote pituitary growth hormone cells. Growth and secretion of hormones, it can also promote the expression of GH gene, thereby promoting the transcription, translation, synthesis and storage of GH gene. It is now generally believed that this disease is an early hypothalamic lesion in children, which damages GHRH cells and ultimately The secretion frequency and secretion of GHRH are reduced, so that the GH cells of the pituitary can not receive enough signals, so that GH cells are poorly developed, and the storage and secretion of hormones are reduced, which leads to the direct cause of damage of hypothalamic GHRH cells. Multifactorial factors, including hypothalamic dysplasia before birth, infection at birth and after birth, and even autoimmune, may also It is related to hypoxia and birth injury at birth. These factors may cause abnormal secretion of hormones in other hypothalamus and pituitary gland, but idiopathic growth hormone deficiency is almost always isolated growth hormone deficiency. After the action of factors, such as the release of other hormones or the release of inhibitory hormones, clinical and laboratory tests should be able to detect the existing hormone detection levels; it seems that the pathogenic factors are not very clear, the above possible causes and GHRH cell selection The sexually impaired link needs further study. In addition, a considerable number of patients have no obvious response or poor response to GHRH treatment. The idiopathic pituitary dwarf has not only the primary lesion of the hypothalamus, but also the pituitary itself may be caused by birth injury. Infection and hypoxia, as well as post-natal infection, autoimmune and other factors cause lesions, because the disease is a benign process, there is currently no detailed information on the physiological, biochemical, and pathological aspects directly related to the hypothalamus and pituitary.

2. Congenital growth hormone deficiency

Patients with congenital GH deficiency have normal height at birth. Careful growth can be found in the first year. There is obvious growth disorder in 1-2 years old. The degree of GH deficiency can be light and light, and the growth of light is slow. Because this type of patients, in addition to GH deficiency, most of the other hypothalamic pituitary hormone deficiency, the child's intelligence is generally normal, CT or MRI can be found in the hypothalamus and pituitary with organic lesions, there may be no special findings; The lesion may or may not have an anatomic abnormality.

Congenital pituitary absent is an autosomal recessive disorder, which is very rare, with severe hypopituitarism and no or only empty sella.

Hereditary growth hormone deficiency is actually caused by the loss of GH gene. These patients have more serious conditions, and growth disorders can be found 6 months after birth. The most common type of such patients is the 7.5 kb base fragment of the GH gene. The pituitary pygmy caused by loss can be divided into four kinds according to the genetic method and the response to treatment and the activity of endogenous growth hormone in the body.

3. Organic lesions of the hypothalamus and pituitary

The hypothalamic and pituitary gland are subject to acquired destruction, which may lead to acquired GH deficiency or reduction. Clinically common cases include tumors (mainly craniopharyngioma), Sheehan syndrome, trauma, infection, pituitary Stroke, hypothalamus and pituitary are exposed to radioactive sources, etc. These children are often accompanied by other symptoms of hypopituitarism. Single GH deficiency is rare; even if the clinical growth is mainly disordered, most other hormones can be detected. which performed.

4. Social psychological factors

Such patients have not been reported in China, the children have normal nutrition, but there may be psychological disorders such as quirks, GH cells in the pituitary are normal, GH secretion levels are low in some patients, and some are normal, mainly due to pulsed secretion of GHRH. Leading to the secretion mode of GH, the frequency of the pulse is related to the abnormality of time and amplitude. It is considered that the child is not suitable for the growing family environment, and there is a contradiction or a feeling of being ill-treated. The living environment is changed, and the growth of most children can return to normal; Such children are less effective with GH or GHRH replacement.

(two) pathogenesis

Most patients have no obvious cause, which is called idiopathic growth hormone deficiency (IGHD). Because many children with IGHD have a history of perinatal lesions (such as premature birth, dystocia, asphyxia, etc.), IGHD ( In some literature, the occurrence of solitary GH deficiency (IGHD) may be associated with perinatal brain damage. Children with IGHD have a poor response to a single GHRH, but most patients with GHRH have blood GH. Can rise to normal, indicating that the lack of GH may be secondary to the lack of GHRH.

Some GH deficiency shows obvious family genetic characteristics, namely familial growth hormone deficiency. According to whether there is other pituitary hormone deficiency, familial GH deficiency is divided into solitary GH deficiency. Isolated growth hormone deficiency and multi-hormone GH deficiency (or combined pituitary hormone deficiency), according to genetic characteristics, isolated GH deficiency is divided into three types: type I is autosomal recessive Inherited, type II is autosomal dominant, type III is X-linked GH deficiency, of which type I is also divided into two subtypes IA and IB, and IA subtype is composed of GH-1 gene (or GH-N gene) Due to deletion, the IB subtype can be caused by mutation of GH-1 gene or by mutation of GHRH receptor gene. The pathogenic gene of type III is still unclear. Like solitary GH deficiency, polyhormone GH deficiency Also classified into 3 types, type I is autosomal recessive inheritance, type II is autosomal dominant inheritance, type III is X-linked GH deficiency, and type I polyhormonal GH deficiency is caused by mutation of Propl gene. Type II is caused by a mutation in the Pit-1 gene. Type of disease genes is unclear.

Most isolated GH deficiency is caused by mutations in the GH-1 gene, which is located on the long arm of chromosome 17, and downstream of the GH-1 gene contains the GH-2 gene (or GI-V gene) and three CS genes, which have high homology with GH-1 gene, these genes can be exchanged unequally, resulting in deletion of GH-1 gene, point mutation of GH-1 gene, deletion of GH-1 gene Causes the body can not synthesize and secrete GH to produce severe IA type GH deficiency (but other pituitary hormones are not affected), this patient lacks GH in the fetal period, but because the growth of the fetus does not depend on GH, the child is in the palace Intravital growth is unaffected, and children are not immune to human GH (hGH) due to lack of GH during development. They are prone to anti-hGH antibodies and are resistant to hGH when receiving hGH treatment. Some patients The GH-1 gene undergoes point mutation or rearrangement, but the patient still expresses GH, and the expressed mutant GH has a certain function (but reduced activity), which is a deficiency of IB type GH. This patient has formed hGH in the embryonic stage. Immune tolerance, exogenous hGH treatment is not easy to produce antibodies, GHRH receptor Mutations weaken the effects of GHRH and cause GH deficiency, which is also a type GH deficiency. In theory, mutations in the GHRH gene can also cause GH deficiency, but so far no mutations have been found in human GH deficiency. .

Why can the mutation of GH-1 gene be expressed as autosomal recessive inheritance (type I) or autosomal dominant inheritance (type II)? The formation mechanism of autosomal recessive GH deficiency is easy to understand. Because the heterozygote contains a normal GH-1 gene, its expression product can maintain normal GH secretion, so heterozygotes do not occur. The formation mechanism of autosomal dominant GH deficiency may be related to the dominant negative effect. The mutant gene of this type of patient may encode a non-functional GH. This non-functional GH can compete with normal GH for GH receptor. Although heterozygous patients have a normal GH-1 gene, the normal GH expression is expressed. The presence of mutant GH loses its function. This is called the dominant negative effect. The dominant negative effect causes the heterozygote to also develop, which is manifested as autosomal dominant inheritance.

Polyhormonal GH deficiency is generally caused by mutations in transcription factors that play important roles in pituitary development and pituitary hormone gene expression. Pit-1 is a pituitary-specific transcription factor that is a member of the POU family and belongs to the helix-turn- Spiral transcription factor, GH-1 gene promoter contains Pit-1 upstream, reaction element, can bind Pit-1 homodimer (complex composed of 2 Pit-1 monomers), Pit-1 dimer and The binding of the Pit-1 response element increases the transcription of the GH-1 gene, thereby promoting the synthesis and secretion of GH. Pit-1 also plays an important role in maintaining the proliferation of pituitary GH cells. Therefore, mutation of the Pit-1 gene may cause Atrophy of GH cells and GH deficiency, Pit-1 protein acts as a dimer, which is the basis for the mutation of its mutation in a dominant way. If the Pit-1 gene from one parent is mutated, the expressed protein loses its function. The dimer of this non-functional mutant Pit-1 protein and the normal Pit-1 protein loses the function of activating the transcription of the GH-1 gene, thereby interfering with the function of the normal Pit-1 protein. This is also a dominant negative phenomenon. Therefore, as long as the patient has When the parental Pit-1 gene is mutated, it can develop disease, so it is dominantly dominant. Pit-1 also plays an important role in the expression of PRL and TSH genes. Therefore, mutation of Pit-1 gene also causes PRL. And the lack of TSH, patients can also have LH, FSH and even ACTH lack.

The transcription factor Prop-1 is required for the expression of Pit-1, and the mutation of Prop-1 can cause a decrease in the expression of Pit-1, which can also cause the deficiency of GH and other pituitary hormones. The transcription factor Lhx-3 (or P-) Mutations in LIM) and HesX1 (or Rpx) can affect the development of the pituitary gland, causing a deficiency in pituitary hormones such as GH.

Some congenital malformations such as no brain malformation, forebrain non-cracking deformity, pituitary absent, neurohypophyseal dislocation, facial midline development defects, arachnoid cysts, etc. can also affect the function of the hypothalamus-pituitary, resulting in GH deficiency.

Tumors of the hypothalamus and pituitary gland, inflammation, bruises, surgery, radiation, etc. can all lead to GH deficiency, which can be collectively referred to as acquired GH deficiency.


Growth hormone deficiency prevention

1. GH deficiency has obvious family genetic characteristics and can be used for chromosome examination.

2. Regular perinatal care to avoid perinatal lesions such as dystocia, intrauterine asphyxia, etc., so as not to cause brain damage.


Growth hormone deficiency complications Complications, stunting

In addition to the above-mentioned manifestations, secondary growth hormone deficiency may be associated with various symptoms of the primary disease. It may be caused by hypothalamic-pituitary tumors, vision loss, visual field defects, and increased intracranial pressure in the later stage. , as well as lethargy, convulsions, etc.


Symptoms of growth hormone deficiency Common symptoms Tone like child glucocorticoid secretion too little amenorrhea hair pale and brown depression cryptorchidism without beard bones closed early

Primary growth hormone deficiency is more common in boys. The child's height and weight are normal at birth, and growth retardation occurs several weeks later. It gradually becomes obvious after 2-3 years old. Its appearance is obviously smaller than the actual age, but the proportion of various parts of the body is still well-balanced. Intelligent development is also normal. The height is lower than 30% of normal children of the same age. A decrease in secondary sexual characteristics and sexual organ dysplasia can occur with age. Secondary growth hormone deficiency can occur at any age. In addition to the above symptoms, there are various symptoms and signs of the primary disease.

Idiopathic growth hormone deficiency is more common in boys, male: female = 3:1, children with elevated birth weight and normal body weight, growth rate slows after 1 year old, growth retardation is more serious than low body weight, low rise At the same age, from the third percentile of growth curve of normal healthy children (or less than two standard deviations), the annual growth rate of height is less than 4cm, and the intelligence development is normal. The child's head is round, his face is childish, his face is fat, his skin is delicate, his hair is slender, his jaw and ankle are stunted, his teeth are delayed and the arrangement is not neat. Although the child grows behind, the proportion of the body is evenly proportioned, which is consistent with his actual age. . Most puberty development is delayed.

Some children with growth hormone deficiency are accompanied by one or more other pituitary hormone deficiencies. In addition to growth retardation, these children have other concomitant symptoms: those with adrenocorticotropic hormone (ACTH) deficiency are prone to hypoglycemia. Thyroid stimulating hormone (TSH) deficiency may have symptoms of mild hypothyroidism such as loss of appetite and inactivity, accompanied by gonadal dysplasia in gonadotropin deficiency, and small penis (ie, straight penis length less than 2.5 cm) By the time of puberty, there are still no sexual organs and secondary sexual development.

Organic growth hormone deficiency can occur at any age, with those caused by abnormal perinatal conditions, often accompanied by symptoms of diabetes. It is worth noting that intracranial tumors have symptoms such as increased headache, vomiting, visual field defects and other symptoms of intracranial pressure and optic nerve compression.


Growth hormone deficiency check

Laboratory inspection:

1. Growth hormone stimulation experiment

The diagnosis of growth hormone deficiency depends on GH. The normal human serum GH value is very low, and it is pulsed secretion. It is affected by various factors. Therefore, blood sampling and blood GH are not meaningful for diagnosis, but if the blood GH level is significantly higher. At normal (>10 g/L), GHD can be excluded. Therefore, children with GHD are suspected of having to undergo a GH stimulation test to determine the function of the pituitary to secrete GH.

The physiological test is a screening test and a drug test is a confirmed test. It is generally believed that during the test, the peak value of GH is <10 g/L, which means that the secretion function is abnormal. The peak of GH is <5 g/L, which is no complete deficiency of GH. The peak of GH is 5-10 g/L, which is a lack of GH. Because of the limitations of various GH stimulation tests, GHD must be diagnosed if the results of two or more drug stimulation tests are not normal. In general, insulin is added to the clonidine or levodopa test. For younger children, especially those with hypoglycemia on an empty stomach, special care should be taken for insulin, which can cause serious reactions such as hypoglycemia and convulsions. In addition, if it is necessary to distinguish whether the lesion is in the hypothalamus or in the pituitary, a GHRH stimulation test is required.

2. Determination of 24H secretion spectrum of blood GH

The peak value of growth hormone in normal people is very different from the base value. The secretion of H in 24 hours can correctly reflect the secretion of GH in the body. Especially for children with GHND, the GH secretion can be normal, but the secretion of 24h is normal. Insufficient, the peak of GH at night is also low, but the program is cumbersome and has a lot of blood draws, which is not intended for patients.

3. Determination of pancreatic nucleus growth factor (IGF-1)

IGF-1 is mainly present in the blood circulation in the form of protein binding (IGF-BPs), of which IGF-BP3 is predominant (more than 95%). IGF-BP3 has co-cooling for transporting and regulating IGF-1, and its synthesis is also affected by The regulation of GH-IGF axis, therefore, both IGF-1 and IGF-BP3 are indicators for detecting the function of the axis. The secretion mode of the two is different from GH, and it is non-pulsed, so it is stable, and its concentration is below 5 years old. Very low, and with age and development performance, puberty peak, girls reach the peak two years earlier than boys, currently can be used as a GHD screening test for children from 5 years old to puberty, this indicator has certain limitations It is also affected by factors such as nutritional status, sexual development and thyroid function, and should be noted when judging the results.

4. Other auxiliary inspections

(1) X-ray examination: bone age is usually assessed by right wrist and metacarpal bone. The bone age of children with GHD lags behind the actual age of 2 years or older.

(2) CT or MRI examination: children who have been diagnosed with GHD, choose head CT or MRI as needed to understand the hypothalamic-pituitary organic lesions, especially for tumors.

5, other endocrine examination

Once GHD is established, other functions of the hypothalamic-pituitary axis must be examined. TSH, T4 or thyrotropin releasing hormone (TRI) stimulation test and luteinizing hormone releasing hormone (LHRH) can be selected according to clinical manifestations. The function of the thalamus-pituitary, thyroid axis, and gonadal axis.

The main diagnosis basis: 1 short stature, height behind the third-percentile of normal children of the same age and same sex, 2 slow growth, growth rate <4cm / year, 3 bone age behind the actual age more than 2 years, 4GH stimulation test It shows that GH is partially or completely lacking, 5 intelligence is normal, and it is commensurate with age, 6 excludes other diseases.


Diagnosis and identification of growth hormone deficiency


Before diagnosing growth hormone deficiency, suspected patients should first determine whether they are gnomes, generally not easy to find within 1 year of age, unless the condition is serious, growth disorders within 1 year of age are not particularly obvious, severe cases appear after 6 months; The patient needs to measure the height and then compare it with the normal value, which is lower than 30% of the normal value. It can also be determined by calculation. The formula is (1 to 12 years old): 80+ age (year) × 5 is lower than 30% of the value can be determined, less than 20% should strengthen observation, especially in the body GH still has a small amount of secretion, the child's length index is short, but there is still a distance from the 30% of the target required for diagnosis.

Diagnosis of growth hormone deficiency, in addition to relying on clinical manifestations, mainly rely on the determination of GH deficiency to rule out other causes of gnomes, causing many reasons for growth and development disorders, and its clinical manifestations are somewhat different from pituitary gnomes, and some are exactly the same.

Differential diagnosis

1. Short stature caused by non-endocrine factors

(1) Constitutional short stature: not a disease, a positive family history, height at birth, normal weight, slow growth in childhood, delayed development of puberty, accelerated growth during puberty, some people are not obvious, adult height is normal or During the normal low-limit, growth retardation period, the child had no facial performance of the pituitary dwarf, normal body shape, normal or slightly delayed bone age, and other laboratory tests were normal.

(2) genetic hereditary dwarfism: related to family, ethnicity, no endocrine dysfunction, normal bone age.

(3) Premature dysplasia: low birth weight infants, some premature infants have been growing with low percentiles after birth, and are still very short after adult. The children's face may be naive, round and even wrinkled. The body is normal, the bone age is normal or slightly delayed, and the endocrine function is normal.

All kinds of serious chronic diseases of the whole body or organs can cause growth disorders in children and adolescents. More serious malnutrition, malabsorption, chronic liver disease, congenital heart disease, chronic kidney disease, chronic lung disease, endocrine examination in dwarfism Before, these issues should be noted or checked.

(4) various short syndromes: congenital or hereditary diseases such as Turner syndrome, Noonan syndrome (pseudo Turner syndrome), Prader-Willi-Lalhert syndrome, Laurence-Moon-Biedle syndrome, and autosomes All kinds of abnormalities can be manifested as short stature in childhood and even in adults; in addition to short stature, they also have their own unique clinical manifestations, which are easier to distinguish from growth hormone deficiency.

(5) bone and cartilage hypoplasia: children with many limb malformations, easy to distinguish.

2. Other shortcomings caused by endocrine factors

(1) Laron gnome: increased blood GH, but defective in liver receptors or receptors, resulting in a decrease in insulin-like growth factor-I (IGF-I); the latter is the main growth factor that promotes growth after birth. The disease is autosomal recessive, and its clinical manifestations are consistent with growth hormone deficiency. The diagnosis depends on the increase of blood GH in the child to make a judgment; the determination of blood IGF-I deficiency or significant reduction, plus GH increase , you can confirm the diagnosis.

(2) Pygmies pygmy: found in Central Africa, Central South Asia and the Atlantic Ocean in the Pygmy population, is autosomal recessive, serum GH normal or increased, but IGF-I decreased, IGF-II Normally, exogenous GH does not improve growth.

(3) Abnormal GH secretion of molecular structure: Rarely, the concentration of immunologically active GH in blood is increased, but its biological activity is decreased or absent.

(4) hypothyroidism: in children with cretinism, mental retardation, abnormal body shape, but some children are atypical, with obvious growth and development disorders, other symptoms are mild, should pay attention.

(5) glucocorticoid hyperactivity: including Cushing's disease, excessive secretion of cortisol from adrenal tumors, and long-term treatment with glucocorticoids, due to various reasons, mainly because a large number of glucocorticoids inhibit GH secretion It inhibits the stimulating effect of interleukin on cartilage growth and causes a negative nitrogen balance, which causes protein synthesis disorder and bone decalcification, so that the bone matrix is formed slowly, calcium salts cannot be deposited, and growth is inhibited.

(6) Diabetes: poor control of childhood diabetes, some children with growth and development disorders, may be due to excessive endogenous glucocorticoids in this part of the child, coupled with insulin deficiency, its protein synthesis is seriously affected, effectively Treatment of diabetes can restore growth. If the child has diabetes, short stature and hepatosplenomegaly, it is called Mauric syndrome.

(7) Diabetes insipidus: Uncontrolled children have growth disorders due to reduced food intake and internal environment and metabolic disorders. After correction, most of them can resume growth.

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