Growth hormone treatment of achondroplasia
Key words: achondroplasia; growth hormone; clinical features;
There are a number of reasons why some children cannot reach the expected adult height. Achilles achoma (achondroplasia, ACH) is a disproportionate gnome of common body, the cause of which is a bone growth disease caused by hereditary achondroplasia. The inheritance or mutation of the coding sequence of the fibroblast growth factor receptor 3 (FGFR3) gene has been confirmed as the cause of most ACH [1-6].
ACH can occur in all species, male and female. The incidence rate is 1 / 20 000 ~ 26 000, 80 or more is sporadic, is a new mutation. Below 20 is familial. The genetic method is: if one parent has ACH, the child’s genetic chance is 25; if both parents have ACH, their child’s genetic chance is
- Another 25 children will inherit the abnormal genes without disease, and the remaining 25 children will be normal and will not inherit the next generation [1-3].
2 etiology and pathogenesis
For more than 10 years, with the wide application of molecular biology techniques, substantial progress has been made in the study of the etiology and pathogenesis of ACH. It was confirmed by linkage analysis that the ACH pathogenic gene was located on chromosome 4 short arm 1 region 6 band 3 subband
(4p16.3), fibroblast growth factor receptor 3 (FGFR3) is in this chromosomal region. Basic fibroblast growth factor
(bFGF) inhibits the mitogenic effect of chondrocytes, differentiation of terminal chondrocytes, and cartilage matrix calcification. FGFR3 has been recognized as the most important regulator of endogenous cartilage growth. The FGFR3 gene coding sequence is genetically or nascently mutated by a single base mutation in two sites, ie, the FGFR3 gene 1 138 guanine (G) is replaced by adenine (A) mutation, another mutation mode of the gene
The guanine (G) at position 1138 of the FGFR3 gene was replaced by a cytosine (C) mutation. Seino et al. Analysis of GFFR3 point mutations in 75 Japanese ACH patients showed that 72 cases were G1138A and 3 cases were G1138C, while mutations were found in the normal control group, which was consistent with the results of Roussceau et al [5-9]. In the vast majority of cases, the genetic or mutation of the FGFR3 gene coding sequence has been identified as the cause of ACH. The above-mentioned molecular genetic engineering techniques will provide new diagnostic tools and classification basis for ACH and its related short stature. This provides a basis for early assessment and prevention of ACH .
3 clinical manifestations and diagnosis
The impact of ACH on patients, families and society is mainly short stature.
ACH is characterized by short limbs, relatively dry, and giant. Infants during pregnancy or at birth can be found to be disproportionate to the limbs, torso and head, and become more typical over time. Japanese statistics show that adult male ACH patients are about 130cm tall and about 120cm female. According to Horton et al., the height of an adult male is 118 to 145 cm, and that of an adult female is 112 to 136 cm. Therefore, there is a significant difference in the final height of untreated ACH patients of different races and genders [2, 3].
According to clinical manifestations, combined with functional tests and imaging studies, the diagnosis and differential diagnosis of ACH is not difficult.
Epidemiological data of 733 children and adults with ACH showed that the ACH mortality rate was more than 2 times higher than that of normal people, and it was more common in infants and young children. In complications, children with hearing loss due to middle ear infections; 20 patients with delayed language; >40 patients over 40 years of age have facial dysplasia due to incomplete tooth closure. Two complications are more noticeable. One is that the occipital foramen becomes smaller and compresses the neck cord, which in turn causes central dyspnea, ventricular enlargement and lower extremity paralysis. If there is clinical manifestation, it should be checked promptly. Decompression and decompression. The other is respiratory disease in young children, including sleep dyspnea, obstructive sleep apnea, cerebral edema, and pulmonary heart disease. Therefore, it is necessary for experienced pediatric, neurology, neurosurgery, respiratory and orthopedic specialists to conduct regular examinations every 2 to 3 months in the first 1.5 to 2 years of the onset of the disease. Evaluation and proper treatment are necessary, especially in growth. Before and after hormone therapy [3, 4].
4.1 Recombinant Human Growth Hormone Therapy Over the past 20 years, growth hormone preparations have been successfully used to treat growth hormone deficiency (GHD) in short children. Short children with normal growth hormone excitatory responses have proven to be of value. Biohormone therapy is beneficial for increasing the final height of Down’s syndrome, achondroplasia, and kidney failure. At present, the clinical application of growth hormone with short stature and puberty is rapidly increasing. Therefore, the reasonable selection of relevant examinations, especially endocrine function tests, to accurately diagnose and differential diagnosis is very important for determining the true indications .
In theory, growth hormone does not increase height in children with chondrodysplasia because the abnormally growing cartilage does not respond to growth hormone , but growth hormone is an important regulator of linear bone growth. In vitro studies have shown that growth hormone is an important factor in the growth and differentiation of chondrocytes. Growth hormone-dependent insulin-like growth factor I (IGF-1) stimulates the proliferation of human chondrocytes in vitro, and growth hormone can increase the IGF-1 response. Based on the above theory, growth hormone can be used for short stature caused by lack of non-growth hormones [13, 14].
As early as the early 1990s, Bridge et al. suggested that although growth hormone concentrations were normal in most patients with skeletal dysplasia, short growth hormone therapy trials have been shown to increase growth rates. Only patients with Downer syndrome have evidence of long-term treatment with growth hormone to increase their height. Growth hormone therapy for 4 to 6 years in patients with ACH has been shown to increase the growth rate of patients. However, the long-term efficacy of growth hormone needs to be further confirmed. Since then, reports of growth hormone therapy for ACH have increased rapidly .
Six children with pre-pubertal ACH were treated with recombinant growth hormone (rhGH), ranging from 211/12 to 85/12 years old, and rhGH was administered subcutaneously daily at a dose of 0.1 IU/(kg·d). After 1 year of treatment, the growth rate of 3 children increased from 1.1cm to 2.6cm, and the other 3 cases did not change. This data shows that GH has significant individual differences in the efficacy of ACH. No side effects were found during the treatment of all children except mild elevation of 2 bone ages. M RI scan of cervical spinal cord and CT scan of the skull base and occipital foramen were normal .
Yamate et al reported 22 patients with ACH, including 7 males and 15 females, with an age range of 3 to 12 years. GH secretion function and GH stimulation test results showed that 17 of the GH excitatory tests were normal, 4 cases of levodopa excited GH were lower than normal, <10ng/ml, and the other 1 showed less than normal CRF stimulation, <20ng/ml . The average GH concentration <5 ng/ml was found in 3 patients during sleep, suggesting a potential GH deficiency with low levels of IGF-1 and bone age delay. All patients had normal serum LH, FSH, TSH, and cortisol stimulation tests. RhGH was used in 11 patients with typical and uncomplicated ACH. Pre-treatment, treatment, and post-treatment blinded studies were performed every 4 months for hematuria, blood biochemistry and blood lipids, serum T4 and TSH, fasting blood glucose, and HbAlc serum calcium, and 3 anti-GH antibodies. No abnormalities were found during regular monthly monitoring. The X-ray measures bone age every 6 months. The diameter of the occipital foramen and the length of the lower limbs were evaluated before and after treatment [17,18].
The results of rhGH treatment in 6 children with ACH showed that GH secretion was normal in 5 patients and GH secretion was impaired in 1 patient, which may be related to obesity. The growth rate before treatment was (3.8 ± 0.7) cm/year, and the growth rate increased to (6.0 ± 1.0) cm/year in the first year after treatment; and (4.4 ± 0.6) cm/year in the second year. l The patient had a satisfactory growth rate after 4 years of treatment .
Forty-two patients with ACH, including 16 males and 26 females, aged 3 to 14 years, had normal hypothalamic pituitary function and were taller at first and second years after rhGH treatment (6.5 ± 1. 8) cm/year, ( At 4.6 ±1.6) cm/year, the growth rate increased by an average of 3.9 ± 1.0 cm/year compared with that before treatment, and there was no abnormal change in body proportion. Therefore, rhGH treatment of ACH is beneficial for 2 years of treatment .
In 18 patients with ACH treated with genotropin rhGH, the dose of rhGH was 1 IU/(kg·week). The growth rate before treatment was (4.1 ± 0.8) cm/year, and (7.28 ± 1.4) cm/year at 6 months after treatment. Whether children with a potential deficiency of GH have better clinical efficacy for rhGH therapy deserve further study. Routine testing of GH secretion before the use of rhGH in all ACH children, including the GH excitatory test is necessary. In another study, 11 patients with ACH had a therapeutic dose of rhGH of 0.04 mg/(kg·week) and a treatment time of 1 year. The average growth rate after treatment was significantly increased compared with that before treatment, which was (5.3 ± 1.6) cm/year and (4.0 ± 1.0) cm/year, respectively. The linear growth rate is (1.8 ± 2.0) cm / year. The long bone growth of rhGH in ACH children was significantly higher than that of the proximal end, which was (1.1 ± 1.6) cm/year and (3.0 ± 1.2) cm/year. No significant side effects were observed during rhGH treatment. The effect of this treatment on the height of the trunk is more effective than the increase in limb length [18, 19].
Stamoyannou et al observed the efficacy and safety of rhGH in 15 children with ACH. Of the 15 children with ACH, 7 were men, aged 4 to 12 years, 8 women, aged 5.7 to 12 years old, received subcutaneous injection of rhGH 1 IU/(kg·week) daily for 2 years, developmental assessment and follow-up The diagnosis was 6 months before treatment, at the beginning of treatment, and at 6 months and 24 months after treatment. Hypothalamic and thyroid function, GH stimulation test, and IGF-1 and IGF binding protein 3 (IGFBP-3) were measured before treatment. Of the 15 children, 3 were abnormal in the GH excitatory test. During the first half of the treatment period, the height of the foot (HV) increased significantly in all children, but the growth rate decreased relatively during the half year after treatment. At the end of the first year of treatment, the HV increase in 13 patients ranged from 3.2 cm/year to 6.9 cm/year (mean 3.7 cm/year, range 1.1 to 8 cm/year). There were no changes in HV in 2 patients. The growth rate of HV was relatively lower in the second year of treatment. Of the 9 patients who were followed up, 7 patients increased by an average of 3.1 cm/year, and 2 patients did not respond to GH therapy. The sitting height/height ratio (SH) did not change throughout the treatment period and there was no significant change in bone maturation. Children with the lowest growth rate before treatment may receive the most satisfactory rhGH treatment. IGF-1 and IGFBP-3 are associated with therapeutic response. However, the final height of GH in children with ACH remains to be further studied .
Follow-up of 35 patients with rhGH [dose range 25.8 to 40 IU/(m2·week), ie 0.04 to 0.08 mg/(kg·d)] for 6 years of treatment of ACH showed that the pre-treatment height SDS was -4.6 (-3.2 ～ -6.5). In the 4 years of treatment, the height of SDS increased every year, ANOVA F was -46.9, P <0.01, but there was no statistical difference between the 5 years and 6 years and the annual height SDS of the first 4 years. Height was significantly increased in the first year of treatment (ANOVA = 4.82, P = 0.001). Age was the most important variable for height SDS during the first year of treatment, r = 0.41, P < 0.001, independent of rhGH dose. The seat height SDS increased significantly more than the subsaccular height SDS. Because the increase in the spine is significantly higher than the rate of growth of the lower extremities, surgical lower extremity prolongation is necessary and beneficial for the relative proportion of the body after adulthood.
Seino et al used randomized clinical controlled trials to observe the efficacy of daily subcutaneous injection of rhGH in 145 patients with Japanese ACH, and compared the effects of different doses of rhGH. After 1 year of rhGH treatment, it can increase the height, height Z integral, growth rate and growth rate Z integral of predevelopmental cartilage hypoplasia. The effect of rhGH dysplasia after rhGH treatment was dose-dependent, that is, different doses of rhGH [0.5 IU/(kg·week), 1.0 IU/(kg·week)], large dose of 1.0 IU/(kg·week), A small dose of 0.5 IU / (kg · week), after 1 year of treatment, can increase the height of the height more effectively and improve the height SDS (from -4.83 ± 1.03 to – 4.57 ± 0. 90, -5.15 ± 1.10 to – 4. 72 respectively). ±1.21). Moreover, compared with before treatment, the height of the 2nd and 3rd years was still statistically different and dose-dependent; however, there was no significant difference between the 4th and 5th years and before treatment. The results of rhGH treatment before development of ACH for 1 to 3 months at 1 interval showed that there was a statistically significant difference in the increase of IGF-1, IGFBP-3 and osteocalcin compared with before treatment, in a dose-dependent manner. During rhGH treatment of achondroplasia, no significant side effects or adverse reactions were found in either short-term (1 year) or long-term (4 years). Therefore, rhGH has a positive effect on ACH, and the effect is dose- and time-dependent. rhGH promotes bone growth by increasing growth rate and height Z integral, which is an effective method for severe growth delay caused by ACH . .
4.2 Surgical treatment rhGH can increase the height of ACH patients, but eventually requires surgical extension to extend the lower limbs, which can increase the height by 12cm. However, surgery is prone to many complications, requiring experienced specialist hospitals and specialists to perform surgery [1, 10].
In summary, the following conclusions can be drawn: 1rhGH treatment of ACH children can increase the growth rate and increase the height, but there are individual differences in treatment effects. The effect of 2rhGH in children with ACH was dose-dependent, ie rhGH 1.0 IU/(kg·week) was better than 0.5 IU/(kg·week). The efficacy of 3rhGH in the treatment of children with ACH was time-dependent, that is, the fastest increase in height during the first half of treatment, 1 year, 2 years.