Short stature (short stat ure) is defined as a child’s height being more than 2 standard deviations below the normal height of an individual of the same race in a similar environment, or below the third percentile of the growth curve of a normal child.
Diagnostic steps of short stat ure
The history of the child includes gestational age at birth, delivery method, length and weight, and the presence of asphyxia and deformity; the mother’s gestation, delivery, pregnancy and birth history, health status during pregnancy, history of illness, exposure to rubella, history of alcohol consumption and smoking, labor and delivery, placenta size, shape and tissue status, and history of spontaneous abortion; the height of the parents and all members of the family, the parents’ puberty and developmental history; the child’s height is less than normal. History of development; whether the child had been discriminated against and abused, or whether there were adverse factors in the environment that affected the child’s psychosocial condition; feeding and appetite. The child’s previous height records were collected, and the height growth curve was drawn.
The physical examination should be standardized, including height, weight, sitting height, finger distance, head circumference, subcutaneous fat thickness, etc. Observe whether the child’s development is proportional, head, face, trunk and limbs are special. The development of muscles, muscle tone, the whole body organs, especially the sexual organs and secondary sexual characteristics were examined.
Laboratory examinations include bone age and frontal and lateral cranial radiographs. If the child is suspected of having skeletal lesions, further examination of the spine, thorax, upper and lower extremities, epiphyseal growth and bone density should be observed. In girls with short stature or mild deformities, karyotype analysis should be done to rule out congenital ovarian hypoplasia. For endocrine disorders or pituitary dwarfism, thyroid function (F T3, F T4 and TSH) and growth hormone (various stimulation tests) should be checked, and IGH1 and IGFBP3 levels should be measured to determine the function of GH-IGF axis. L HRH stimulation test and HCG stimulation test can be performed in patients with suspected delayed pubertal shortening and pituitary dysfunction.
Differential diagnosis of short stature
GH deficiency is the most common cause of dwarfism in children. Short stature due to lack or deficiency of pituitary GH secretion is called pituitary dwarf, also known as pituitary short stat ure, and may be accompanied by multiple pituitary hormone hypofunction. According to the defective function of hypothalamus-GH-IGF axis, the etiology can be divided into:
1, GH secretion disorder:
(1) Cortical dysfunction: GH neurosecretory dysfunction (growt hormone neurosecretory dysf unction, GH2ND) and neurotransmission defects;
(ii) Hypothalamic GH deficiency: such as inflammation, trauma, tumor, infiltrative lesions and glucocorticoid or sex hormone induced and idiopathic in the central nervous system;
(3) Pituitary GH deficiency: such as anatomical abnormalities, traumatic brain injury, GH gene mutation and idiopathic, etc.
2.GH post-secretory disorders:
(1) Presence of GH antibodies;
②Significant increase of GH binding globulin;
(iii) GH receptor defect;
④The presence of anti-GH receptor antibodies;
⑤ Post-GH receptor defect.
3.Defective IGF1 synthesis:
①Defective IGF1 production site;
②Changes in IGF1 binding protein;
(3) Presence of IGF1 antibody.
4, IGF1 insensitivity:
①Decrease in the number of IGF1 receptors;
②Defective IGF1 receptor;
(iii) Presence of IGF1 antibody;
④Defective post-IGF1 receptor;
⑤ Target tissues are not sensitive to IGF1.
Some children with GH deficiency have a history of obstructed labor, asphyxia or malposition at birth, with breech or full-term births being the most common. The growth of GH deficiency is normal at birth, but the growth is slowed from 5 months after birth, and the slow growth is usually noticed after 2 to 3 years of age. The growth slowdown increases with age, and the body shape is more infantile than the actual age. The appetite is low since childhood. Typically, the child is short, with relatively high subcutaneous fat, accumulation of abdominal fat, round face, slightly protruding forehead, small jaw, normal upper and lower volume, proportional limbs, high pitch voice, annual growth rate of height at school age is less than 5 cm, in severe cases only 2 cm to 3 cm, height deviation below the normal mean – 2 SD. The child’s intelligence was normal. Teething and bone age were delayed. Adolescent development was mostly delayed. The difference in skeletal age is usually more than 2 SD. In the presence of other pituitary hormone deficiencies, there is usually a lack of gonadotropin, which results in no sexual development, small penis and testicles in boys, no breast development in girls, and primary amenorrhea; in the presence of ACTH deficiency, there is often skin pigmentation and severe hypoglycemia; in the presence of thyroid hormone deficiency, there is hypothyroidism. Some cases are associated with polyhydramnios and partial enuresis.
Intrauterine growth retardation (IUGR) is usually diagnosed in full-term infants weighing less than 2.5 kg. Currently, there are two types of IUGR: the normal type of IUGR, which is characterized by homogeneous short stature, and the asymmetric short stature (Russell-Silver syndrome). The general type of IU GR has no gender differences and is not associated with dysmorphism except for proportional dwarfism. Children with IU GR may have inadequate or abnormal GH secretion on endocrine examination. It has been reported that a certain percentage of children with IU GR have GH peak below 10 μg/ml after drug stimulation.
In children with IU GR, the peak value of GH after drug stimulation is less than μg/ml. The parents may have a history of delayed puberty. The more pronounced the delay in sexual development, the more significant the family history tends to be. Endocrine function tests are generally normal, but GH levels may be partially or temporarily deficient after pharmacological stimulation. However, the delayed spontaneous puberty may still allow the child to reach normal height and sexual maturity, so this is a variant of normal growth. Most of the children are born with normal length and weight, and there is no abnormality in the first few years, but height growth and maturation decreases every year, especially before puberty or when puberty is approaching (2-3 years before 10-11 years old for boys and 9-10 years old for girls). The onset of sexual characteristics can be delayed by several years, from 16 to 18 years for males and 14 to 16 years for females, and the delayed onset of puberty is associated with delayed bone age, which also parallels growth. This disorder is characterized by a late onset of natural puberty followed by accelerated height growth and a progressive sexual development process that is not different from that of normal children. It can reach adult lifetime height at 20 years of age or later, and has normal reproductive function.
Idiopathic dwarfism (idiopat hic short stat ure) requires the exclusion of all known causes, no organic disease, the child has a proportional body shape, normal length and weight at birth, and is short and proportional. The peak of natural GH secretion (physiological secretion) and drug-induced secretion is within the normal range, and the short stature is usually not severe, but can be at the level of -2. 2 (±0. 6) SD. In recent years, GH treatment has been tried and it is believed that although the recent height growth is slightly accelerated, the lifetime height still cannot reach the standard. Therefore, for familial dwarfism without GH deficiency, it is still controversial whether it is necessary to use long course expensive GH drug treatment.
The main cause of nutritional deficiency retardation or nutritional dwarfism is inadequate nutritional intake due to poverty, but it is also seen in children with subjective self-restricted diet and unreasonable nutritional intake that leads to growth involvement. The weight/height ratio is often similar to that of non-nutritional dwarfism (familial dwarfism, somatic dwarfism), although the child’s weight is lower than that of the same age, making it difficult to differentiate. Nutritional deficiency growth retardation can be caused by organic or non-organic disorders. Nutritional deficiency growth retardation can occur at any age, and the degree of dwarfism is less severe than that of GHD, without the typical physique of pituitary dwarf, but with clinical manifestations of malnutrition. The endocrine examination often shows the separation of GH level and IGF1 level, which may be related to the decrease of liver protein synthesis. The patient is behind in bone age. The growth retardation is temporary due to the lack of nutrition, and the growth can be accelerated by restoring sufficient nutritional intake and adjusting the diet structure to make it reasonable.
Psychosocial short stat ure often occurs in families with parents who are not in good relationship, divorced or single-parent families, and the psychosocial frustration affects the function of hypothalamus-GH-IGF axis, and GH secretion may be normal or lacking. The mechanism of this disorder is complex and may be related to chronic nutritional deficiency and GH neurosecretory dysfunction. Typical symptoms are growth arrest, delayed puberty, and delayed bone age; in addition, poor diet, sleep, or intestinal malabsorption, lethargy, reluctance, and changes in eating habits and behavior. The disorder can occur in school-aged or young children. Blood levels of IGF1, ACTH and glucocorticoids may be low, while thyroid hormones may be normal.
Laboratory tests
Although there are some racial and gender differences in epiphyseal development, and variations among normal children, there is generally a pattern. The growth of height depends mainly on the changes of the long bone epiphysis, including the morphology of the ossification center and the final fusion with the backbone, so we can judge the age and predict the height from the epiphysis development. The age of the bones is usually determined by x-ray of the wrist, and sometimes the shoulder, elbow, knee and ankle joints are also selected. In addition, frontal and lateral cranial radiographs can be taken to observe the size of the butterfly saddle and changes in the skull and cranial suture.
The serum GH value is low, fluctuating and pulsatile, with a short half-life, so the random blood measurement is often unable to distinguish normal people from GH deficiency, so the one-time specimen measurement is meaningless. Clinically, the diagnosis is often made by drug provocation test (Table 3). Fasting for 8 hours is required before the stimulation test, but water fasting is not necessary. If the peak GH is < 5μg/L, it is a complete GH deficiency; if the peak GH is (5.1-9.9) μg/L, it is a partial GH deficiency; if the peak GH is ≥10μg/L, it is a normal response.
IGF1 measurement is another important indicator of GH-IGF-chondrogenic axis function by mediating the growth effect of IGF1. The IGF1 concentration is age-dependent and is also affected by thyroxine, prolactin, cortisol and nutritional status. The IGF1 measurement has some differential diagnostic significance.
IGFBP3 is the linker protein of IGF1, 95% of IGF1 in circulating blood binds to IGFBP3, and the binding has high affinity and specificity, which can adjust the effect of IGF1 on cell proliferation, metabolism and mitosis. GH deficiency, the presence of GH antibodies, severe liver disease and malnutrition can all cause a decrease in IGFBP3 levels.
MRI can clearly show the size of the volume of the pterygoid saddle, the size of the anterior and posterior pituitary lobes and the ectopic position, which is important for the diagnosis of GH deficiency. According to the data of Shanghai Institute of Pediatric Medicine and Xinhua Hospital, among 27 cases of GH deficiency, all of them showed that the anterior pituitary lobe was shrunken and the normal part of the posterior pituitary lobe disappeared in 96% of cases, among which 44% were displaced, 37% were disappeared and 20% were interrupted.
Chromosomal examination should be performed routinely for female dwarfism with delayed puberty to exclude chromosomal disorders such as Turner syndrome.
Treatment
Currently, the treatment of short stature is mainly based on the identification of the cause of the disease. GH treatment is available for both idiopathic and secondary GH deficiency. GH treatment for GH deficiency can achieve a normal adult height within the mean value of – 2 SD.
Most scholars currently recommend a weekly dose of (0.5 – 0.7) U/kg, with 0.1 U/kg injected subcutaneously each night before bedtime. The maximum effect is at the beginning of the first 6 months to 12 months, long-term application, the growth rate is slowed down, then the dose can be increased each time 0. 05U/kg, but the total amount should not exceed 0. 2U/(kg ・24h). In 20 cases treated with imported GH at the Shanghai Institute of Pediatrics, the growth rate accelerated from <4 cm/year to 9.2 cm-13.7 cm/year, with an average growth rate of 12 cm/year. the effect of domestic GH treatment was similar to that of imported drugs.
Second, the application method is subcutaneous injection, the drug peak time is 2h ~ 4h, blood clearance time is 20h ~ 40h. The volume of drug injected subcutaneously is generally 0.5ml~1.0ml, which can be injected in the upper arm, front side of thigh and around the umbilicus of abdominal wall. The younger the age of starting treatment, the better the effect.
GH treatment complications
1.Local reaction: Local skin reaction is related to the purity of GH preparation and individual reactivity, generally showing skin redness, swelling, itching, and in severe cases, heat and pain, reaching a peak in the second to third day, then gradually subsiding and disappearing after one week.
2, antibody production: antibody production is closely related to the purity of the preparation, about 1-4% of cases can affect the growth.
Hypothyroxine (T4)emia: T4 concentration is normal before treatment, but may decrease after treatment. According to the Shanghai Institute of Pediatric Medicine, after 7 months of treatment, hypothyroidism reaches 45%. Occasionally, facial swelling, weakness, sleepiness and decreased academic performance are seen clinically, but most patients do not show significant signs. Treatment should be thyroxine supplementation.
4.Blood transaminases: generally mildly elevated, gradually disappear with drug discontinuation. With the large availability of rhGH, the treatment of rhGH has gone beyond growth hormone deficiency, and Turner syndrome has shown some efficacy with growth hormone therapy. The weekly dose of rhGH is slightly higher, 1. 0 U/kg, and treatment should be started at an early age, and should be discontinued if the patient is older than 14 years and has an annual growth rate of less than 2. 5 cm. There are some reports of GH treatment in non-GH deficient dwarfism, but because of the tendency of GH to accelerate maturation in bone age, the effect on lifetime height is not conclusive and the final height benefit of the child cannot be confirmed. Nandrolone phenylpropionate is a commonly used anabolic steroid to promote growth, which significantly accelerates bone age and accelerates epiphyseal fusion, but does not significantly improve final height.