Congenital incomplete testicular development in children

　　1. Etiology

　　1. This condition is caused by an abnormal sex chromosome, with most patients having an extra X chromosome, hence the most common peripheral blood leukocyte karyotype is 47, XXY, or mosaic 47, XXY/46, XX or 47, XXY/48, XXXY, and even more X chromosomes, such as 49, XXXXY. The X body examination of the oral mucosa is positive in 93% of the 47, XXY karyotypes.

　　2. The various karyotypes of this symptom are the result of non-separation of sex chromosomes or sex chromosome monomers during cell maturation division or during the cleavage of the zygote. Chromosome gene marker studies show that non-separation of oocytes is more than twice that of sperm. The above sexual chromosome abnormalities are more common in pregnant women of advanced age, which may be due to the aging of oocytes, weakened centromere longitudinal splitting force, or spindle orientation. There are indications that the more X chromosomes in this symptom, the more serious the hyalinization of the seminiferous tubules, the more severe the stromal hyperplasia and fibrosis, and the more affected the intellectual development, the mechanism of which is unknown. Some scholars have hypothesized that the genes of X chromosomes have an adverse effect on testicular development, so the main pathological characteristics of this symptom are incomplete seminiferous tubules, small testes, unable to produce sperm or sperm extremely rare, so infertility. Interstitial cells are in adenomatous clusters, and the lipid substances and secretory granules contained in the cells are reduced. Some cases have abnormal electroencephalogram findings, suggesting mild organic brain dysfunction, whether primary or secondary to endocrine dysfunction has not been determined.

　　II. Pathogenesis

　　1. Congenital incomplete testicular development is a congenital disease of incomplete or non-developing testicular spermatogenic development, and patients often seek medical attention due to infertility or undeveloped external genitalia in physical examination, and then are diagnosed by karyotype examination.

　　2. The common feature of different types of this disease is that the number of sex chromosomes is one or more than one X chromosomes more than the normal XY. The extra X chromosomes have adverse effects on both testes and signs, especially more on signs. The more X chromosomes, the more obvious the maldevelopment of the testes, the more severe the symptoms, the poorer the intellectual development, and other malformations are often more frequent. Since the Y chromosome has the testis determining gene (TDF), all patients have a Y chromosome, so the patients have a male phenotype, but the excessive number of X chromosomes leads to varying degrees of feminization.

　　3. There are many karyotypes of congenital incomplete testicular development. In 62 cases reported by Wang Defen and others in China in 1987, 71.0% were 47,XXY, 24.2% were 47,XXY/46,XY mosaics, and approximately 3.2% and 1.6% were 48,XXXY and 48,XXYY, respectively. The formation of these karyotypes is due to the non-separation of sex chromosomes or sex chromosome monomers during cell maturation division, or the non-separation of sex chromosomes or sex chromosome monomers during the cleavage of the zygote. Chromosome gene marker studies suggest that non-separation of oocytes is more than twice that of sperm. Abnormalities of sex chromosomes are more common in pregnant women of advanced age, which may be due to the aging of oocytes, weakened centromere longitudinal splitting force, or spindle orientation. Some analyses indicate that 60% of patients are due to maternal chromosomal non-separation, and 40% are due to paternal chromosomal non-separation. Non-separation of chromosomes during meiosis is approximately 83% likely to occur during the first meiotic division, and 17% during the second meiotic division.

　　4. Due to the increase in X chromosomes, the testes do not develop, the penis is short, plasma testosterone levels decrease, FSH and LH levels increase; insufficient androgen secretion. The increase in FSH may be due to damage to the Sertoli cells, resulting in reduced inhibin secretion. Low testosterone levels indicate that the interstitial cells of the testes in patients with this disease have reduced testosterone secretion function, which necessarily leads to compensatory increase in LH. Electron microscopy shows that there are abnormal mitochondria and endoplasmic reticulum in the interstitial cells of the testes of patients, which may be the material basis for substances that interfere with testosterone biosynthesis.

　　1. Androgen deficiency: Eunuchoid body type, normal or slightly taller stature, longer lower limbs, normal or short penis, low libido. About 97% of patients are infertile, with osteoporosis and reduced muscle strength.

　　2. Up to 13% of patients may have varicose veins, thrombosis, and chronic leg ulcers, which may be due to reduced fibrinolysis caused by androgen deficiency, rather than vascular anatomical changes.

　　3. Learning, language, and intellectual disabilities.

　　1. The incidence of this disease is quite high, but many patients have no symptoms or discomfort except for infertility, so they will not seek medical attention, making it difficult to detect. Patients have a male phenotype, a slender body, a tall stature, a greater finger span than height, and often enlarged breasts. The feminization of breasts accounts for about 40%. In the 47, XYY and 48, XXYY karyotypes, patients with two Y chromosomes show more obvious tall body type, and puberty development is often delayed. Due to the absence of sperm, they generally cannot reproduce (there are occasional exceptions).

　　2. Physical examination may show不明显 male secondary sexual characteristics, no beard, no Adam's apple, fair skin, small testes, and a small penis. There may be cryptorchidism or hypospadias, and poor development of pubic hair.

　　3. Patients may have characteristics such as being solitary, shy, inactive, timid, and lacking male characteristics. In the standard 47,XXY karyotype, about 25% show moderate intellectual development delay, manifested as language and learning disorders. This condition lacks obvious symptoms before puberty and is not easy to recognize. If routine karyotype analysis is performed on children with intellectual delay or behavioral abnormalities, early diagnosis can be made.

　　4. Congenital incomplete testicular development in childhood can be diagnosed due to cryptorchidism or small testes, but most cases are not serious, lack characteristic symptoms, or are easily overlooked due to physical examination negligence. Generally, during the adolescent growth period, due to the lack of testicular development and incomplete masculinization, some patients come for consultation due to female breast development or infertility.

　　Chromosomal abnormalities in congenital incomplete testicular development are more common in pregnant women of advanced age, and relevant preventive measures for genetic diseases can be referred to:

　　1. Prohibition of marriage between close relatives to avoid high-risk pregnancy.

　　2. Pre-marital examination is conducted to detect genetic diseases or other diseases that should not be married.

　　3. The detection of carriers is determined through means such as mass screening, family investigation and pedigrees analysis, and laboratory tests to determine whether it is a genetic disease and to determine the mode of inheritance.

　　5. Prenatal diagnosis Prenatal diagnosis or intrauterine diagnosis is an important measure of preventive eugenics.

　　One. Cytogenetic testing

　　1. Oral mucosal X chromosome examination:The X chromosome chromosome is also known as the X body (Barr body). Normally, the number of X bodies is equal to the number of X chromosomes minus 1. Since normal males have only one X chromosome, the X body examination is negative. However, patients with 2 or more X chromosomes can have 1 or more X bodies in their oral mucosal cells. This examination method is simple, and the result can be obtained after smearing and microscopic examination. It can be used as an initial screening test for sex chromosome abnormalities and can be performed in places without cell culture conditions, but it cannot perform accurate karyotype analysis.

　　2. Chromosomal karyotype analysis:

　　(1) Chromosomal karyotype analysis of peripheral blood lymphocytes: In normal male somatic cells, the sex chromosomes are XY. The standard karyotype of this disease is XXY, a sex chromosome trisomy. 80% of the karyotypes are the standard type 47,XXY or a variant of the standard karyotype, such as 48,XXXY. 48,XXYY. 49,XXXXY. 49,XXXYY. 15% are mosaics, with karyotypes including 47,XXY. 46,XY. 47,XXY. 46,XX. 47,XXY. 46,XY. 45,X. 47,XXY. 46,XY. 46,XX, etc.

　　(2) Chromosomal karyotype analysis of amniotic fluid cells: To prevent the birth of children with congenital sex chromosome diseases, amniocentesis is performed between the 16th and 20th weeks of gestation to draw amniotic fluid cells, which are then cultured and analyzed for fetal chromosomal karyotype. Abnormal karyotypes can be terminated promptly, reducing birth defects.

　　Two. Fluorescence in situ hybridization

　　In the second trimester of pregnancy, chromosomal karyotype analysis of the fetus is required for both peripheral blood lymphocytes and amniotic fluid cells, which requires cell culture before karyotype analysis, thus taking a long time. Fluorescence in situ hybridization detection does not require cell culture and can directly perform hybridization detection on interphase cells, shortening the diagnosis time. This method is more advantageous for prenatal diagnosis, as it can directly hybridize with trophoblast cells and amniotic fluid cells, reaching a conclusion in 1 day. If there are abnormalities, the pregnancy can be terminated, and the time of ending the pregnancy can be提前.

　　Three. Biochemical examination and other tests

　　1. The patient's serum testosterone level is low, with weakened hypothalamic-pituitary feedback inhibition, elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the pituitary, and lower serum testosterone levels than normal; the luteinizing hormone-releasing hormone (LHRH) stimulation test shows increased FSH response and normal LH response; the human chorionic gonadotropin (HCG) stimulation test shows a low testosterone response.

　　2. The patient's seminal fluid does not contain sperm, and the pathological examination of the testicular living tissue shows degeneration of the seminiferous tubules and hyperplasia of the stromal cells.

　　3. Abdominal ultrasound examination, electrocardiogram, and X-ray chest film examination are performed to understand the presence of other malformations and abnormalities.

　　Pay attention to the selection of food, provide nutritious, light and easy-to-digest food such as lotus root powder, milk, egg custard, rice porridge, etc. It is also necessary to ensure nutrition and food intake in daily life, eat less greasy or overly sweet food, and avoid eating cold food. If allergic to certain foods, avoid them. Prohibit close relatives from getting married, avoid high-risk pregnancy, and premarital examination is to find out hereditary diseases or other diseases that should not be married.

　　I. Treatment

　　1. Patients should start androgen therapy from 11 to 12 years old. Generally, cyclopentylproplonate ester is used, starting with an intramuscular injection of 50mg each time, once every 3 weeks, and increasing the dose by 50mg every 6 to 9 months until reaching the adult dose (250mg every 3 weeks). For older patients, the starting dose and incremental dose can be increased to achieve faster effects. Currently, testosterone undecanoate (also known as Andriol), a derivative of testosterone with strong androgenic and protein-synthesizing effects, is commonly used in China. Each vial contains 250mg and is injected once a month for 4 consecutive months. After injection, it is slowly absorbed through the lymphatic system, with a peak blood drug concentration time of 2 days and a duration of effect of 1 month. The oral dosage form contains 40mg per tablet, which is easily absorbed by the gastrointestinal tract, reaching a peak within 2.5 to 5 hours and returning to the original level 10 hours later. The initial oral dose is 120 to 160mg/d, taken in three doses, for 2 to 3 weeks, then changing to a maintenance dose of 40 to 120mg/d. Since undecanoate testosterone is absorbed through the lymphatic system and not through the liver, it has no effect on liver function.

　　2. Starting from adolescence,雄激素treatment is often seen to improve their learning skills, narrow the gap with normal children, become more cheerful, and enhance self-confidence, but some may regress after stopping treatment.

　　II. Prognosis

　　Patients with congenital incomplete testicular development can be initially judged of their prognosis according to their karyotype. The more X chromosomes in the karyotype, the worse the prognosis, followed by early diagnosis and early treatment, which is also very related to the improvement of the child's symptoms.