2 1 trisomy syndrome is often called congenital idiot in China, and it is the earliest and most common chromosome aberration syndrome reported. 1866, Langdon Down, a British doctor, first described the case clinically. 1959, French cytogeneticist Lejeune and others confirmed that the cause of the disease was an extra G chromosome. Later, most scholars thought that chromosome 2 1 was the most common patient. In 1965, Yunis et al. proved by autoradiography that chromosome 22 is actually the most common patient of this disease. The Paris Conference of 197 1 year specially changed the numbers of chromosomes 2 1 and 22 in order to take care of the previously recorded congenital idiot as 2 1 trisomy.
The incidence of neonatal 2 1 trisomy syndrome is 1/600 ~ 1/800. Its main clinical manifestations: the patient's face is particularly dim (Figure 2-6- 17), such as low nose, wide eye distance, small eye fissure, upward inclination of the outer corner of the eye, epicanthus, iris hypoplasia, strabismus and so on. Small ears, often low, auricle deformity. The jaw is small, the mouth is often half-open, the tongue is large and overhanging, and the mouth is drooling. Excessive flexion of limbs and low muscle tension, so it is also called soft idiot. The fingers are short, the little finger is invaginated, and the middle phalanx is dysplasia. About 50% patients are accompanied by congenital heart disease, of which ventricular septal defect accounts for about half. Patients often have dermatoglyphic changes, such as hand piercing (1/2 ~ 1/3) and increased atd angle. All patients showed different degrees of growth retardation. Male patients may have cryptorchidism, but no one has given birth. Female patients occasionally have fertility, and 1/2 children will get sick. The patient's IgE level is low, which is prone to respiratory tract infection. The incidence of acute leukemia in patients was significantly higher than that in control group (10 ~ 20 times).
Mental retardation is the most prominent and serious manifestation of 2 1 trisomy syndrome. IQ is usually between 25 and 50. Patients with better intelligence can learn to read or do manual work; They can learn to do more work through training. Poor people have difficulties in language and self-care.
Children who are lively, likable, easy to imitate and love music tend to be rigid in behavior, and their abstract thinking ability is the most damaged.
The diagnosis of 2 1 trisomy syndrome mainly depends on chromosome examination. According to the different karyotypes of patients, they can be divided into the following three types:
About 92.5% of patients with (1)2 1 trisomy belong to this type. The patient's karyotype is 47, XX(XY), +2 1 (Figure 6- 18), that is, there is one more chromosome 2 1 than normal people. The main reason of this disease is that chromosome 2 1 does not separate during gamete formation. Studies have shown that among patients with 2 1 trisomy, 80% are due to the fact that the mother's germ cells are not separated during meiosis (80% of them are in the first meiosis stage) and 20% are due to the fact that the father's germ cells are not separated during meiosis (60% of them are in the first meiosis stage and 40% are in the second meiosis stage).
The incidence of 2 1 trisomy syndrome increases with the mother's age. According to the statistics of Carter and Evans, the probability of having 2 1 trisomy syndrome in women over 35 years old is obviously increased, and the probability of having 2 1 trisomy syndrome in women over 45 years old is even more obvious (Table 6- 1). This may be related to the easy chromosome segregation of eggs in elderly pregnant women. Some data show that the father's age is also related to the onset of this disease. When the father is over 39 years old, the risk of having children increases. However, opinions in this regard are not very consistent.
(2) Chimeric type is rare, accounting for about 2.5% of patients with congenital stupidity. The reason for this type is that chromosome 2 1 does not separate during the cleavage of fertilized eggs in the early embryonic development. The karyotype of the patient is 46, XX(XY)/47, XX(XY), +2 1. If chromosome segregation occurs earlier, the greater the proportion of abnormal cell lines, the more serious the clinical symptoms, and vice versa. Therefore, most of the clinical symptoms of these patients are not as serious and typical as 2 1 trisomy.
(3) Translocation patients account for about 5% of all patients with congenital idiocy. Its characteristic is that the redundant chromosome 2 1 does not exist independently, but is transferred to a chromosome in group D or G through robertsonian translocation. Therefore, the total number of somatic chromosomes in these patients is still 46, but in fact, an extra chromosome 2 1 is attached to one chromosome, thus showing the same clinical symptoms as the typical 2 1 trisomy. D/G translocation is the most common type of congenital idiocy. For example, 14/2 1 translocation, the patient's karyotype is 46, XX(XY), a 14,+t (14q; 2 1q). That is, a chromosome 14 is missing, and the long arm 14 and the long arm 2 1 form a translocation chromosome. About 3/4 of this translocation is new, and 1/4 is inherited by one parent. In the latter case, the mother is more likely to be a translocation carrier than the father. The karyotype of translocation carriers is 45, XY(XX), 14, -2 1,+t (14q; 2 1q). Although the total number of chromosomes is one less, the total amount of genetic material is not much different from that of normal people, and it is basically in a balanced state, so it is also called a balanced translocation carrier. Such carriers may have no abnormal appearance, but among the daughters born after marriage with normal people, 1/4 is a normal person, 1/4 is a translocation-type congenital idiot, 1/4 is a translocation carrier, and 1/4 lacks a 2655.
3/4 fetuses with 2 1 trisomy syndrome have spontaneous abortion during pregnancy, mostly in the early pregnancy, and only about14 fetuses can survive until birth. The average life expectancy of patients after birth is 16.2 years, 50% died before the age of 5, 8% can be over 40 years old, and 2.6% can be over 50 years old. (Meow-meow syndrome)
In 1963, Lejeune et al. first reported three cases. Chromosome abnormality was a partial deletion of the short arm of chromosome 5. The incidence rate is 1/50000 of newborns, ranking first among children with abnormal autosomal structure, with more girls than boys.
The most important clinical feature of this syndrome is that children cry like cats, so it is also called meow syndrome. Patients with mental retardation and growth retardation. Small head, round face, wide eye distance, and oblique outer corner. Low ears, small chin, cleft palate. About 50% cases have congenital heart disease, finger pointing and whitening of medullary joints. The karyotype is 46, XX(XY), del(5)(p 15). This shows that the short arm of chromosome 5 is partially deleted, and the breaking point of deletion is at p 15, that is, the part of short arm 1 far from region 5 has been deleted. (1) Congenital testicular hypoplasia syndrome (Klinefelter syndrome)
Klinefelter of Massachusetts General Hospital and his colleagues first described this syndrome in 1942, so it was called Klinefelter syndrome. In 1956, Bradbury et al. found that X chromatin (Barr corpuscle) was positive in this kind of patients. In 1959, Jabobs and Strong confirmed that the patient's karyotype was 47, XXY (Figure 6-20). That is, there is one more X chromosome than normal men, also known as 47XXY syndrome.
The incidence of this disease in male newborns is 0. 13%. That is, there are l patients among 850 people, accounting for 1/20 of male infertility. The main clinical features of the patient are: the patient is male in appearance, asymptomatic in childhood, and the symptoms become more and more serious after puberty. The patient is slim and weak. Male genitalia, short penis, small testicles or cryptorchidism. Testicular tissue section showed that renal tubules were glassy and could not produce sperm, so they were infertile. About 25% of patients can develop into female breasts by puberty. Axillary hair and pubic hair are rare or absent; The beard is sparse, the Adam's apple is not obvious, the subcutaneous fat is developed, the skin is delicate like a woman, and the temperament and posture tend to be feminine. Some patients have mental retardation, but most of them have normal intelligence. Some patients are mentally abnormal or prone to schizophrenia. Patients' mothers are usually older. The karyotype of 80% ~ 90% patients is 47, XXY；; About 10% ~ 15% is chimeric, and the common karyotypes are 46, XY/47, XXY；; 46, XY/48, XXXY, etc. If the proportion of 46, XY normal cells in chimera patients is large and the clinical manifestations are light, they can have fertility. And 48, XXXY；; 49, XXXXY, etc. Due to the function of redundant X chromosomes, the more X chromosomes, the more serious the symptoms.
About 60% of the reasons for the generation of 47, XXY are due to the fact that the X chromosome did not separate during meiosis during the formation of its mother germ cells. 40% is because my father's XY chromosome is not separated.
After the disease is diagnosed, androgen replacement therapy in adolescence can promote the development of secondary sexual characteristics and improve the psychological state of patients. If the curative effect is not good, do not use it for a long time. Male breast development can be surgically removed.
(2) Congenital ovarian hypoplasia syndrome (Turner syndrome)
In 1938, Turner reported 7 cases of short stature, immature sexual development, webbed neck and cubitus valgus. 1954 Polani et al. found that many cases of Turner syndrome have X chromatin negative and ovarian hypoplasia. It was not until 1959 that Ford discovered that the patient's karyotype was 45, x, which was the earliest sex chromosome abnormality found. So Turner syndrome is also called 45, X or 45, XO syndrome.
The incidence of Turner syndrome in newborn girls is 1/250 o- 1/5000. In spontaneous abortion embryos, the incidence can be as high as 7.5%. According to the data, it is speculated that 98% of 45, X embryos will have spontaneous abortion, and only about 2% of those with mild dysplasia can survive.
The patient's appearance is female, with short stature (120 ~ 140 cm) and low hairline. About 50% patients have webbed neck, stiff face, cubitus valgus, shield chest, wide breast spacing, undeveloped breasts until puberty, nipple dysplasia, cord gonad, external genitalia of infants and primary amenorrhea. Some patients have mental retardation. Karyotype analysis showed that the patient's karyotype was 45, and X, X chromatin and Y chromatin were all negative (Figure 6-2 1). About 15% of them are chimeras with karyotypes of 45, X/46 and XX. When the proportion of abnormal karyotype is small, the clinical signs are atypical, such as short stature, primary amenorrhea, cord gland and so on. Some patients may have menstruation. If 46, XX cells are dominant, the phenotype looks like normal individuals, and they can get pregnant, but their fertility is reduced.
The reason is that during the gamete formation, one of the parents does not have a sex chromosome. About 75% of chromosome loss occurred in the paternal side, and about 10% occurred in the early cleavage after zygote, resulting in various chimeras. Except for a few patients who died of severe malformation in the neonatal period, they generally survived. Treatment with sex hormones in adolescence can promote the development of secondary sexual characteristics and reproductive organs, menstrual cramps and improve the psychological state of patients. Some people treat short stature with low doses of estrogen, androgen and growth hormone. Each drug may be effective in the short term, but the treatment of a large number of patients is still under study.
(4) trisomy x syndrome and multiple x syndrome
1959, Jacobs and others first described a woman with three X chromosomes, and called it a superwoman. This is a common chromosomal abnormality in women. The incidence of newborn girls is about11000. It accounts for about 4/ 1000 of female mental patients. There is no obvious abnormality in trisomy X women, and about 70% cases have normal development of secondary sexual characteristics in adolescence and can give birth. About 30% patients have irregular menstruation, primary or secondary amenorrhea or premature menopause, breast dysplasia and abnormal ovarian function, and about 2/3 patients have slightly lower intelligence and are prone to mental illness. Except 47, XXX, some patients have chimera karyotype, and the symptoms are generally mild. Theoretically, half of the offspring of 47, XXX females should have 47, XXX or 47, XXY karyotypes. But in fact, more than 30 children born to women above 10 47 and XXX have normal karyotypes. The explanation for this phenomenon is that in the first meiosis of women, the nucleus with XX almost always enters the polar body and is eliminated. There are also patients with 4 or even 5 X chromosomes. Generally speaking, the more X chromosomes, the more serious the mental damage and developmental deformity. Some data show that the mothers of patients with this disease are older than the control group. Almost all the extra X chromosomes come from the non-segregation of maternal meiosis, and mainly in the first time.
(5) XYY syndrome
196 1 was first reported by Sandberg and others, also known as super male. 1965, Jacob et al. examined the chromosomes of 197 male prisoners with violent behavior tendency, and found that 7 cases were such patients, and proposed that the existence of two Y chromosomes might be related to infringement, thus attracting people's attention.
The incidence of male is about1/750 ~1500. The incidence of males in prisons and mental hospitals is relatively high, accounting for about 3%. The main clinical manifestations of the disease are mostly men with normal phenotype, tall and often exceeding 180cm, and the incidence frequency tends to increase with the increase of personal height. Most of them have fertility, and occasionally hypospadias, cryptorchidism, testicular hypoplasia, spermatogenesis process disorder and fertility decline. These patients have normal intelligence, but they are grumpy, rude and aggressive, and often commit aggressive crimes. At this time, the EEG showed abnormality, and the age of crime was relatively young, with an average of 13.438+0 years.
In addition to the 47, XYY karyotype, there are 48, XYYY；; 49, XYYYY type patients, but rare. These patients are impatient and have poor mental development, finger deformities.
47. The cause of XYY karyotype is mainly due to the fact that the Y chromosome did not separate during the second meiosis formed by the father's sperm. It is reported that two men, such as 47 XYY, each gave birth to a son of 47 XYY.
Third, fragile X chromosome syndrome.
1968 Lubs found the first fragile x chromosome syndrome in a family with familial x-linked mental retardation. But it was not until Girand and Harvey in 1976 and 1977 that the relationship between this fragile X chromosome and mental retardation was determined. Fragile X chromosome (fra X) means that the chromosome at Xq27.3 is filamentary, resulting in a satellite-like structure at its connecting end. Because this filamentous part is easy to break, it is called fragile part. Fragile X chromosome syndrome is the highest incidence of X-linked mental retardation syndrome, second only to Down syndrome.
This disease is mainly seen in men, and the incidence rate is11250. Because men are hemizygotes, as long as there are fragile sites on the X chromosome, they can show the disease. About 10 ~ 20% of male mental retardation cases are caused by this syndrome. It used to be thought that the phenotype of female carriers was normal. However, it is known that about13 of female heterozygotes have mild mental retardation. It is estimated that female carriers account for about 0.5‰ of the female population.
The most typical clinical manifestations of male patients are moderate and severe mental retardation, with IQ of 0 ~ 50. Large testicles, language disorder, special facial features, large ears, larger head circumference than normal, prominent mandible, and hypoplasia in the middle face.
It has been proved that the genetic basis of fragile X chromosome syndrome is not chromosome breakage, but DNA amplification, which is caused by a large number of GGG (arginine coding) sequences in the fragile part of X chromosome. The number of GGG repeats at this locus is 30 ~ 40 in normal people, while the number of GGG repeats in patients with fragile X chromosome syndrome is as high as hundreds or even thousands. Androgyny means that some patients have different degrees of androgyny in gonad, internal and external reproductive organs and accessory sexual characteristics.
(1) True hermaphroditism
Patients have hermaphroditic gonads, and about 40% patients have ovaries on one side and testicles on the other. One side of 40% is ovary or testis, and the other side is ovary and testis; About 20% patients have ovarian testicles on both sides. Patients with different external genitalia and secondary sexual characteristics are between the sexes, and their appearance can be male or female. The karyotype of true hermaphroditism can be 46, XX, 46, XY or 46, XX/46, XY.
(2) Pseudohermaphroditism
There is only one kind of gonad in the patient's body, but the external genitalia has bisexual characteristics. If the gonad is testis, it is male pseudohermaphroditism; If the gonad is ovary, it is female pseudohermaphroditism. The reason is either abnormal sex hormone levels during sexual development or abnormal maternal hormones during embryonic development (such as using progesterone in large quantities to protect the fetus). Male pseudohermaphroditism is called feminization, and its karyotype is 46, XY, X chromatin negative and Y chromatin positive. It can be divided into two categories: androgen insensitivity syndrome (testicular feminization syndrome) and incomplete male pseudohermaphroditism. The former has obvious feminization of external genitalia and secondary sexual characteristics; The latter is lighter, showing that the penis is short, the testicles are small or cryptorchidism, and the breasts develop into women. The karyotype of female pseudohermaphroditism is 46, XX. X chromatin is positive and y chromatin is negative. Congenital adrenal hyperplasia (AR) is very common. Among them, 2 1 hydroxylase defect (type ⅰ) is the most common, followed by 1 1 hydroxylase defect (type ⅱ). Some patients are also accompanied by water and salt metabolism disorder.
Drug or surgical treatment can partially improve the clinical manifestations of hermaphroditism patients.