Introduction
Growth hormone(GH) is a major factor in the body's growth. There are many factors affecting height. In children and adolescents, the secretion or deficiency of pituitary GH will cause obvious obstacles to the growth of patients. Other causes include malnutrition, ethnic inheritance, psychosocial factors, and a variety of physical diseases including endocrine and non-endocrine diseases. If the height is lower than the same ethnic group, less than 30% of the same age, or the adult height is less than 120cm, it is dwarfism.
Cause
(1) Causes of the disease
1 Idiopathic growth hormone deficiency accounts for the vast majority of such patients, and the specific reasons are not fully understood. 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. With comparable intracellular growth hormone storage, these children responded well to treatment with GHRH and its analogs. GHRH can not only promote the growth and secretion of hormones in pituitary cells, but 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 causes damage to GHRH cells. Eventually, the frequency and secretion of GHRH are reduced, so that GH cells in the pituitary do not receive enough signals, resulting in dysplasia of GH cells. The storage and secretion of hormones is reduced. The direct cause of damage to hypothalamic GHRH cells now appears to be multifactorial, including prenatal hypothalamic dysplasia, infection at birth and postnatal, and even autoimmune, possibly with hypoxia at birth, Related to birth injury. These factors are entirely likely to cause abnormal secretion of hormones in other hypothalamus and pituitary gland, but idiopathic growth hormone deficiency is almost always an isolated growth hormone deficiency. After the patients are affected by the causative 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 may The cause of the loss of GHRH cell selectivity remains to be further studied. In addition, a considerable number of patients have no significant 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 due to birth injury, infection and hypoxia at birth, and postnatal infection. Factors such as autoimmunity cause lesions. Since the condition of the disease is a benign process, detailed information on the physiological, biochemical and pathological aspects directly related to the hypothalamus and pituitary is still lacking.
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, and the degree of GH deficiency can be light or heavy. Lighter growth is also more obvious, 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, or no special findings; the lesion may or may not have anatomic abnormalities.
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 the GH gene. Such patients are more severely ill, and growth disorders can be found 6 months after birth. The most common of these patients is the pituitary dwarf caused by the loss of 7.5 kb base fragment in the GH gene, which can be divided into four types according to the genetic response and the response to treatment and the activity of endogenous growth hormone in vivo (Table 1). ).
3. The hypothalamic and pituitary carcinogenic lesions of the hypothalamus and pituitary are subject to acquired destruction, which may lead to the acquisition of acquired GH deficiency or reduction. Common clinical conditions include tumors (mainly craniopharyngioma), Sheehan syndrome, trauma, infection, pituitary apoplexy, hypothalamic and pituitary gland exposure to radioactive sources. These children are often accompanied by other symptoms of hypopituitarism, a single GH deficiency is rare; even if the clinical growth disorder, most of them can detect other hormone deficiency.
4. Psychosocial factors These patients have not been reported in China. The child's nutrition is normal, but there may be psychological disorders such as quirks. The GH cells in the pituitary are normal, and the GH secretion level is low in some patients, and some of them are normal, which may be related to the pulsed secretion abnormality of GHRH, which leads to the secretion mode of GH, the frequency of pulse and the abnormality of time and amplitude. Most people think that the child is not suitable for the growing family environment, there is a conflict or ill-treated psychology, change the living environment, most children's growth can return to normal; such children with GH or GHRH substitution is less effective.
(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, isolated GH deficiency is also abbreviated as IGHD) may be associated with perinatal brain damage. related. Children with IGHD have a poor response to a single GHRH, but if GHRH is given repeatedly, most patients with blood GH can rise to normal, indicating that GH deficiency may be secondary to GHRH deficiency.
Some GH deficiency manifests a distinct family genetic trait, termed a hereditary or familial growth hormone deficiency. According to whether there is a deficiency of other pituitary hormones, familial GH deficiency is classified into two types: isolated growth hormone deficiency and multihormone GH deficiency (or combined pituitary hormone deficiency). According to genetic characteristics, isolated GH deficiency is divided into three types: type I is autosomal recessive, type II is autosomal dominant, and type III is X-linked GH deficiency. Type I is also divided into two subtypes, IA and IB. The IA subtype is caused by the deletion of the GH-1 gene (or GH-N gene), which can be caused by both the GH-1 gene mutation and the GHRH receptor gene mutation. The type III pathogenic gene is still unclear. . Like solitary GH deficiency, multihormone GH deficiency is also classified into type 3, type I is autosomal recessive, type II is autosomal dominant, and type III is X-linked GH deficiency. Type I polyhormonal GH deficiency is caused by mutation of Propl gene, type II is caused by mutation of Pit-1 gene, and the pathogenic gene of type III is unclear.
Most isolated GH deficiency is caused by mutations in the GH-1 gene. The GH-1 gene is located on the long arm of chromosome 17, and the downstream of the GH-1 gene contains the GH-2 gene (or GI-V gene) and three CS genes, which have high homology with the GH-1 gene. These genes can be unequally exchanged, resulting in the deletion of the GH-1 gene. Point mutations can also occur in the GH-1 gene. Deletion of the GH-1 gene can cause the body to fail to synthesize and secrete GH, resulting in severe IA type GH deficiency (but other pituitary hormones are unaffected). This type of patient lacks GH during the fetal period, but since the growth of the fetus does not depend on GH, the child's intrauterine growth is not affected. Children lack immune GH during development and therefore do not develop immune tolerance to human GH (hGH). They are highly susceptible to anti-hGH antibodies and are resistant to hGH when receiving hGH. Some patients have point mutations or rearrangements in the GH-1 gene, but the patient still expresses GH, and the expressed mutant GH has a certain function (but reduced activity) and is IB type GH deficiency. Such patients have developed immune tolerance to hGH during the embryonic period, and exogenous hGH treatment is not easy to produce antibodies. Mutations in the GHRH receptor attenuate 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 heterozygotes contain a normal GH-1 gene, and its expression products maintain normal GH secretion, heterozygotes do not develop. The mechanism of formation of autosomal dominant GH deficiency may be related to the dominant negative effect. Mutant genes in such patients may encode a non-functional GH that competes with normal GH for GH receptors. Although a heterozygous patient has a normal GH-1 gene, the normal GH expressed by it loses its function due to the presence of mutant GH. This is the so-called 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-helix transcription factor. The upstream of the GH-1 gene promoter contains Pit-1, a response element that binds to a Pit-1 homodimer (a complex of two Pit-1 monomers). Binding of the Pit-1 dimer to the Pit-1 response element increases 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 can cause atrophy of GH cells and deficiency of GH. The Pit-1 protein functions in a dimeric form, which is the basis for its mutation to be inherited in a dominant manner. If the Pit-1 gene from the parental side is mutated and the expressed protein loses its function, the dimer of the 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 normal Pit-1 protein. This is also a dominant negative phenomenon. Therefore, as long as the patient has a mutation in the Pit-1 gene from either parent, it can develop disease, so it is manifested as dominant inheritance. Pit-1 also plays an important role in the expression of PRL and TSH genes. Therefore, mutations in the Pit-1 gene also cause a deficiency in PRL and TSH. Patients may also have LH, FSH or even ACTH deficiency.
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, and thus can also cause a deficiency of GH and other pituitary hormones. Mutations in the transcription factors Lhx-3 (or P-LIM) and HesX1 (or Rpx) can affect the development of the pituitary, leading to a deficiency in pituitary hormones such as GH.
Some congenital malformations such as no brain malformation, forebrain non-cracking malformation, pituitary dysplasia, neurohypophyseal dislocation, facial midline developmental defects, arachnoid cysts, etc. can also affect the function of the hypothalamus-pituitary, resulting in GH deficiency.
Tumors, inflammation, bruises, surgery, radiation, etc. of the hypothalamus and pituitary can all cause GH deficiency, which can be collectively referred to as acquired GH deficiency.
symptom
Children with idiopathic growth hormone deficiency often have normal body length and body weight at birth. After a few months, growth and development are delayed, but they are often not detected. The difference between children and children of the same age is more obvious after 2 to 3 years old, but growth It does not stop completely, but the growth rate is extremely slow, generally not more than 4 to 5 cm per year. Adults generally do not exceed 130cm in height. The bones are childish, the bones are not fused for a long time, and the teeth are mature. The body is generally well-balanced. After adulthood, the body shape and appearance of the child are still maintained. The skin is fine and dry, wrinkles, and the subcutaneous fat can be slightly full.
From the patient to adolescence, the sexual organs are not developed, and the second sexual characteristics are absent. The male genitalia is small, similar to the young child, the testicles are small, mostly accompanied by cryptorchidism, and no beard; the female manifests as primary amenorrhea and the breast is not developed. Sexual organ development and secondary sexual characteristics may occur in individuals with single growth hormone deficiency, but are often significantly delayed. Some patients still have a lack of TSH and/or adrenocorticotropic hormone (ACTH), but most are only found during endocrine hormone testing.
The mental development is generally normal, and the academic scores are indistinguishable from those of the same age. However, after the elderly, they are often depressed and unhappy, and they have a feeling of inferiority.
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, and below 20% should be observed. In particular, there is still a small amount of secretory GH in the body, and the child's length index is short, but there is still a distance from the 30% of the target required for diagnosis.
Diagnosing growth hormone deficiency, in addition to relying on clinical manifestations, relies mainly on the determination of GH deficiency to rule out gnomes caused by other causes. There are many reasons for growth and development disorders, and their clinical manifestations are quite different from pituitary gnomes, and some are exactly the same.
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 The normal low limit. During the growth retardation period, the child had no facial manifestations of pituitary pygmy, 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) Prenatal dysplasia: After birth, some low-weight children and premature babies have been growing with low percentiles and still very short after adults. The child's face may have naive, round face, and even fine wrinkles, normal body shape, normal or slightly delayed bone age, and normal endocrine function.
A variety of serious chronic diseases of the whole body or organs can cause growth disorders in children and adolescents. More serious are malnutrition, malabsorption, chronic liver disease, congenital heart disease, chronic kidney disease, chronic lung disease. Before the endocrine examination of dwarfism, these aspects 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 for growth after birth. The disease is autosomal recessive, its clinical manifestations are consistent with growth hormone deficiency, and the diagnosis depends on the increase in blood GH in children to make a judgment; the determination of blood IGF-I deficiency or significant reduction, plus GH rise High, you can confirm the diagnosis.
(2) Pygmies pygmy: found in the Pygmy ethnic group in Central Africa, Central South Asia and the Atlantic Ocean, is autosomal recessive. Serum GH is normal or elevated, but IGF-I is decreased, IGF-II is normal, and exogenous GH cannot 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, cretinism, mental retardation, and abnormal body shape. However, some children have atypical performance, with obvious growth and development disorders, and other symptoms are mild, which should be noticed.
(5) Hypercorticosteroids: including Cushing's disease, excessive secretion of cortisol from adrenal tumors, and long-term treatment with glucocorticoids. The reasons are manifold, mainly because a large number of glucocorticoids inhibit GH secretion, inhibit the stimulation of growth hormone on the growth of cartilage, and cause negative nitrogen balance, protein synthesis disorders and bone decalcification, such bone matrix formation Slowly, calcium salts cannot be deposited and growth is inhibited.
(6) Diabetes: The control of childhood diabetes is not good, and some children have growth and development disorders. The reason may be that there are too many endogenous glucocorticoids in this part of the child, and the lack of insulin, the protein synthesis is seriously affected. Effective 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 can resume growth.
complication
In addition to the above-mentioned manifestations, secondary growth hormone deficiency may be accompanied by various symptoms of the primary disease. Caused by hypothalamic-pituitary tumors, vision loss, visual field defects, increased intracranial pressure, as well as lethargy, convulsions, etc. may occur.
treatment
(a) treatment
Pituitary dwarfism is a disease of growth hormone deficiency. If the cause is recovery after trauma and small tumors are surgically removed, it is expected to restore the normal secretion of growth hormone.
1. The vast majority of patients' own growth hormone secretion can not be restored, the need for exogenous growth hormone replacement, in order to achieve normal height. Fortunately, growth hormone is not a hormone necessary for human survival. After the treatment reaches the height of the person, the growth hormone deficiency does not need to continue to replace.
Due to the species specificity of growth hormone, animal growth hormone cannot be used by the human body, and only human growth hormone can be used. Before the 1980s, most of the growth hormone extracted from the pituitary of dried acetone powder may cause neuropathy after 10 to 15 years of use, mainly subacute spongiform encephalopathy (Creutzfeldt-Jacob disease). It was banned from use after 1985. Modern molecular biology has developed rapidly. Before the growth hormone extracted from the pituitary gland of human corpse was banned, the human growth hormone gene was genetically engineered into the plasmid of Escherichia coli to produce human growth hormone. It was clinically applied in the early 1980s and became a commodity supply market.
The use of human growth hormone and the timing of use are more advocated. When the growth is active, the response to treatment after the bone age exceeds 10 years old is poor, and the dose to be used is large, but as long as the long bone callus is not closed, the injection of growth hormone is effective; growth hormone Although the effect is poor with the increase of bone age, the results of clinical and animal tests show that the efficacy and dose are positively correlated to some extent.
The recommended dose is 0.1 U/kg (or 2.5 mg/m2), 3 intramuscular or subcutaneous injections per week. At the beginning of the increase in bone age, the number of injections can be increased to 5 times a week, the dose is unchanged, or the dose is increased.
Efficacy: After treatment with the above dose, the growth hormone level in the blood can reach 40mg/ml, and the growth hormone in the blood rises accordingly. Within 1 year of application, the growth rate increased significantly, and the growth was chasing curve. Generally, the growth rate is 10-15 cm in the first year, and the growth rate is declining every year, and some patients can be invalid. Therefore, it is recommended to continue to use drugs within 2 years to achieve the best effect of growth hormone therapy, catch up with the growth height, 2 years later, if the growth momentum is good, continue the original treatment; if significantly slow, consider intermittent therapy: use half Stop for 2 to 3 months from month to month to maintain a certain blood concentration of growth hormone and restore the sensitivity of growth hormone receptors, maintain normal growth momentum, and add some other drugs, treatment until growth stops.
Factors influencing the efficacy: antibody formation, some patients have higher antibody titers, but the titer decreases after 2 to 3 months of withdrawal, and the effect is restored when the growth hormone replacement therapy is used, but the antibody titer can rise again; Patients should be treated intermittently. The treatment period is usually 2 to 4 weeks. When malnutrition is used, the requirements for nutrition are increased after using growth hormone, and it needs to be balanced. When patients with glucocorticoids have pituitary pygmy, glucocorticoids are banned. Even if there is a growth hormone antibody, it is not recommended because the glucocorticoid for treatment far exceeds the physiological requirement.
In the mid-to-late 1980s, GHRH has been used in idiopathic pituitary dwarfism with genetic engineering. It turns out that most idiopathic pituitary dwarfs respond well. It is usually treated with GHRH before growth hormone replacement. There are a variety of uses, useful GHRH1 ~ 40 10 ~ 20μg or GHRH1 ~ 29 8 ~ 10μg, every 3h injection at night, the effect is good; useful 2 times / d, the effect is worse than the former; there is a continuous pulse pump treatment The dosage used is small and the effect is good. There is not much experience, and there is a certain degree of difficulty in treatment.
Synthetic IGF-I, even for the Laron dwarf, is not as effective as people's expectations, and is not as effective as GH.
2. In addition to the above alternative treatments, it is necessary to use some combination therapy, such as adequate nutrition, adequate sleep and exercise. Some drugs not only have synergistic effects with growth hormone, but also promote growth by themselves, but their side effects and therapeutic effects are not ideal when used alone.
(1) Androgen: can promote the secretion of growth hormone, accelerate protein synthesis, and is associated with rapid growth of puberty, but after 2 to 3 years of treatment, this effect is weakened, and can promote healing of the callus, and eventually the height is still short. The use time should be properly grasped, and the effect is not good too early or too late. Nowadays, there are many androgen preparations, generally those which have strong effects on protein synthesis and weaker androgenic effects should be selected. The usage and dosage should be paid attention to when using, and liver function should be checked.
(2) Thyroxine: Thyroxine has the function of promoting cell metabolism and growth, but it can promote the body's maturity, promote the premature healing of the epiphysis, and ultimately affect the height. Because the role of growth hormone should be maximized when the thyroid function is normal, a small dose of thyroxine can be added when using growth hormone replacement therapy.
(3) Human chorionic gonadotropin: mainly used for those who have not been elevated after the above treatment to promote puberty development.
(4) Others: some trace elements such as zinc, as well as traditional Chinese medicine.
(two) prognosis
1. If the disease cannot be diagnosed and treated in time, it will lead to a significant short stature in adulthood and an increase in the incidence of cardiovascular disease, and there are quite a few cases with gonadal dysplasia, central hypothyroidism, and adrenocorticotropic hormone ( ACTH) deficiency. Therefore, the growth hormone deficiency dwarfism (GHD) that cannot be treated will seriously affect the future work, study, marriage, psychology and quality of life. If early treatment is available, the height can be reached within the normal height range. In addition, it also plays an important role in maintaining muscle vitality, improving heart function, delaying aging, preventing and treating osteoporosis, and treating obesity.
2. In the hypothalamic-pituitary tumor, there may be vision loss, visual field defect, and the phenomenon of increased intracranial pressure, as well as salivation and convulsions.
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.
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