The main knowledge of human gonadal development comes from the understanding of the X and Y chromosomes. The central principle is that the Y chromosome (primarily the SRY gene on the Y chromosome) determines the formation and development of the testes. The testes produce androgens, which promote penis enlargement, muscle development and other masculine expressions. The XX chromosome, on the other hand, determines the formation of the ovaries. The ovaries produce large amounts of estrogen, which promotes breast development and other female secondary sexual expression. When chromosomal sex (XY or XX), gonadal sex (ovaries or testes), internal genital sex (prostate, fallopian tubes, uterus), and external genital sex (penis, urethral opening, clitoris, vaginal opening) are inconsistent, it is called a “disorder of sexual development”. The differential diagnosis of sexually differentiated disorders is often analyzed from these four levels. The diagnosis of abnormal sexual development is very difficult, and about 50% of patients are not diagnosed. Studies in the last decade have revealed that many gonadal development-related genes (e.g. DAX-1, DMRT1, SOX-9 genes) or their promoters (SOX-9 promoter) have abnormal copy numbers and can lead to disease. There are many genes in autosomes that are involved in gonad formation and development, such as SOX9, FOXL2, and DMRT2 genes. When large segments of autosomes containing these genes are lost or duplicated, the dose of gene expression is doubled or deficient, leading to testicular or ovarian developmental disorders and clinical manifestations of abnormal sexual development. In this article, we will describe the important link between chromosomes and sexual development in five aspects: genetic characteristics of chromosomes X and Y; clinical characteristics of Turner syndrome (45, XO); clinical characteristics of Cranfelt syndrome (47, XXY); SOX9 and testicular development; DMRT2 and gonadal development; Genetic characteristics of chromosomes X and Y Because chromosomes X and Y contain many genes related to sex development Because the X and Y chromosomes contain many genes related to sex development and spermatogenesis, they have been named “sex chromosomes”. Each sex chromosome has two parts. The majority of the area near the mitotic point is called the “sex chromosome region. In this region, the X and Y chromosomes each contain different genes, so there is little exchange of genetic material between the two chromosomes. The part of the chromosome located in the long and short arms (both ends) is called the “pseudo-autosomal region” (Figure 1). In this region, the X or Y chromosomes contain the same alleles and can therefore exchange genetic material with each other (one of the properties of autosomes), hence the name “pseudo-autosomal region”. Mutations occurring within the sex chromosome region are prone to develop because they lack the genetic compensatory effect of the other chromosome. For example, the KAL-1 gene is located in the “sex chromosome region” of the X chromosome. In 46XY males, mutations in this gene can lead to congenital hypogonadotropic hypogonadism in males [6]. In contrast, in females 46XX, KAL-1 is functionally abnormal and able to be compensated by the other X chromosome. Therefore there are no clinical manifestations and they are carriers of the causative gene. In 46,XX females, one of the two X chromosomes in each cell is inactivated randomly, forming a “baculovirus”. In fact, of that inactivated chromosome, only the “sex chromosome region” is actually inactivated and the genes inside are not expressed, while the genes in the “autosomal-like region” are not inactivated and still exert biological effects. For example, the SHOX gene is located at the end of the short arm of the X and Y chromosomes in the “autosomal-like region 1 (PAR1)”, and SHOX gene expression is dose-dependent, with insufficient doses resulting in short stature. In 46XX women, both SHOX genes located in PAR1 are expressed, so height is not affected. In contrast, in 45,XO patients (Turner syndrome), the clinical manifestation of short stature occurs because of the absence of one X chromosome (or the absence of part of the X chromosome), resulting in a halving of the SHOX gene dose expression. The X chromosome contains many genes related to gonadal development and gonadal axis function, such as androgen receptor, KAL1, DAX1, SOX3, etc. In 46XY males, androgen resistance due to androgen receptor mutations can cause varying degrees of hypermasculine expression or even fully feminine vulvar and breast development. In chromosome 46XY males with mutations in the DAX1 gene, the clinical manifestations are congenital adrenocortical dysplasia and congenital hypogonadotropic hypogonadism, in which the DAX1 protein has antagonistic effects on testicular development. In males with chromosome 46XY, an overexpression of DAX1 doses will inhibit testicular development and result in female vulva (also known as “sexual inversion”). The Y chromosome is the shortest of the 46 chromosomes and contains many important genes related to gonadal development, including SRY, AZF, etc. SRY (sex-determining region Y) was the first transcription factor identified to determine testicular development and is currently considered to be the most important determinant of male sex development. mutations, can result in the absence of testicular development and the appearance of a female vulva. On the other hand, when the X and Y chromosomes are exchanging genetic material, the SRY-containing fragment may be transferred to the X chromosome. This X chromosome, which carries the SRY gene, causes 46 XX (one X chromosome containing SRY) patients to exhibit testicular development and male external genitalia. Recent studies have revealed that SRY is not the only factor that determines testicular development, but is one of the important factors in the signaling pathways that promote testicular development. For example, SRY promotes testicular development by promoting SOX9 factor expression, which further promotes testicular development. If the SOX9 gene is absent or expression is reduced, patients with chromosome 46 XY still exhibit testicular development disorders. another important factor in chromosome Y is AZF, whose mutation or deletion can cause spermatogenesis disorders in male patients. Figure: Pattern of sex chromosomes X and Y: Note: PAR (pseudo-autosomal region) stands for “autosome-like region”. In the XX cell line, the PAR genes are not inactivated; in the XY cell line, there is an exchange of genetic material between the PAR alleles of the X and Y chromosomes; 46, XO Turner syndrome Chromosome 45, XO is the most common chromosome number abnormality resulting in abnormal gonadal development, called “Turner syndrome”. About half of patients have the classic karyotype 45XO and about a quarter have the 45XO/46XX karyotype (chimerism). Other karyotypes, including loss of the long arm of an X chromosome, loss of the short arm, isobaric chromosomes, and circular X chromosomes, can present with similar characteristic clinical features. 7% of aborted children have karyotype 45XO, and patients present primarily with dwarfism and primary amenorrhea. Other manifestations include multiple facial nevi, elbow ectropion, cervical webbing, shield chest, and lymphedema. Almost all patients with Turner syndrome are dwarf, and without intervention, the average height of the patient population is approximately 3525 px. The mechanism of dwarfism is related to an insufficient dose of SHOX gene. A recent case report of a patient with Turner syndrome who was significantly taller because of duplication of a fragment containing the SHOX gene confirms the role of the SHOX gene in stature growth. The characteristic endocrine abnormalities of the patient are markedly elevated levels of gonadotropins (FSH and LH) and very low levels of estradiol. Patients may often have a combination of varying degrees of hypothyroidism. Although an increased incidence of diabetes mellitus has been reported in the literature in this population, clinical observations in our center did not reveal this trend. Treatment of Turner syndrome includes the following: Growth hormone therapy is started early, before epiphysis closure, to help patients achieve a better lifetime height. If the epiphysis is already closed, long-term cyclic sex hormone replacement therapy can be administered to allow patients to obtain normal secondary sex characteristics development as well as a normal sex life. With donor eggs and assisted reproductive techniques, patients have the possibility of obtaining a pregnancy. 47XXY Klinefelter syndrome Clinical presentation: Before puberty, patients with Klinefelter syndrome present only with a small testicular volume and a gradual decrease in the number of spermatocytes in the testes. Patients are most often seen for the development of significant breast development during puberty. The typical pathological changes in the patient’s testis are vitellogenesis of the varicocele, absence of spermatogenesis, and a marked increase in the number of interstitial cells. Because of the marked increase in interstitial cells, the patient’s testosterone is often at low or normal levels. Depending on the karyotype, there are two main categories: classic and chimeric. In classic Klinefelter syndrome, the karyotype is 47,XXY, with typical clinical manifestations, while in chimeric patients, the karyotype is diverse, such as 47XXY/46XY, and the clinical manifestations vary widely. The mechanism of karyotype 47,XXY formation is attributed to chromosome non-segregation during meiosis of gamete formation. This nondisjunction occurs in about 40% of fathers and 60% of mothers. The chimeric karyotype occurs due to chromosomal nondisjunction during mitosis in the syngeneic cells after sperm-egg fusion. This phenomenon can occur in both normal syngeneic cells with karyotype 46, XY, and abnormal syngeneic cells with karyotype 47, XXY. The most obvious endocrine alteration in Klinefelter syndrome is a marked increase in serum FSH and LH levels. Of these, elevated FSH levels are the most pronounced, reflecting persistent damage to the varicocele. During pubertal development, testosterone levels may be normal; around age 25, testosterone levels decrease to half of control values, but fluctuate widely. Mammary gland development is a common manifestation in patients and is the result of an elevated serum estrogen/androgen ratio. the incidence of diabetes mellitus in patients with Klinefelter syndrome is 20%. The prevalence of obesity and metabolic syndrome is significantly higher than in the general population. A recent study showed that at least three metabolism-related transcription factors were significantly elevated in the peripheral blood of Klinefelter patients, but these factors were not located on the X chromosome. This suggests that the XXY karyotype may affect the metabolism of substances in the body by influencing the expression of certain metabolism-associated transcription factors on other autosomes. In terms of treatment: recent studies have shown that there may be insular spermatogenic cells surviving in the testis and therefore sperm may be obtained by minimally invasive microscopic incision of the testis for sperm extraction. About 30-50% of patients are found to have surviving sperm that can be used for IVF. This offers a new treatment option for such patients to solve their fertility problems. If testosterone levels are significantly lower, androgen supplementation is available. Testosterone replacement may improve osteoporosis, weakness, erectile dysfunction, and social interaction skills. Some patients with Klinefelter syndrome have personality and thinking abnormalities, and psychological support for patients and families should be enhanced. SOX9 and testicular development SOX9 transcription factor, located at the end of 17q; SRY factor promotes testicular formation by regulating SOX9 gene expression and thus testicular formation. In patients with chromosome 46XX, a duplication of the fragment containing the SOX9 gene, resulting in SOX9 overexpression, can promote testis formation and lead to abnormal sexual development. Similarly, in males with chromosome 46XY, if the SOX9 factor is under-expressed (haploinsufficient dose), testis formation cannot be promoted. Therefore, during chromosome examination, attention should be paid to the presence of abnormal chromosomal segments at the end of 17q. DMRT1 and gonadal development DMRT1 is a newly identified important transcription factor that regulates gonadal development. We report a 2-year-old patient with female genitalia and a karyotype of 46XY, der(9) t(7;9) (q35, p24) and 46XX, t(7;9) (q35, p24) in the mother; 46XY in the father; microarray comparative genomic hybridization (aCGH) showed that the patient was 46XY, dup(7), (q35-q36.3) ; del(9), (p24.3-q23); duplication at the long arm portion of chromosome 7 (144741153-159098761), about 14.37 Mb long; deletion at the short arm portion of chromosome 9 (10001-9733061), about 9.72 Mb long, and the deletion included 8 genes including DMRT1. These results suggest that the deletion of a small fragment at the end of chromosome 9 causes testicular dysplasia, female vulvar expression, developmental delay, mental retardation, and metabolic abnormalities. This disease is also known as “9p deletion syndrome” and is associated with abnormal testicular development and insufficient dose of DMRT1. DMRT1 (OMIM: 602424) is an abbreviation for Doublesex and mab-3 related transcription factor 1. It is located at the end of the short arm of human chromosome 9 0.84-0.97 Mb. The biological function of this gene is highly conserved, and its homologs are involved in sex differentiation in nematodes, Drosophila, fish and birds. Recent hotspot studies have shown that induction of excessive ovarian DMRT1 gene expression not only drives down ovarian-specific FOXL2 expression, but also promotes morphological transformation of granulosa cells to testicular mesenchymal cells. Conversely, reducing DMRT1 expression in the testis promoted the transformation of the mesenchymal cell morphology of the testis to ovarian granulosa cells. These studies suggest that DMRT1 plays an important role in maintaining the cellular morphology and function of the differentiated gonads. In humans, DMRT1 gene expression is gonad-specific, sexually dimorphic expression, and dose-dependent. In haploid (hemizygous) dosage underexpressed states, XY individuals exhibit testicular dysgenesis and vulvar feminization. Summary Numerous transcription factors regulating testicular development and androgen action are present on the X and Y chromosomes. Functional defects or excessive doses of expression of these factors, or deletions and increases in the number of sex chromosomes, can lead to abnormal gonadal development. Common chromosomal abnormalities disorders include Turner syndrome (45, XO) and Klinefelter syndrome (47, XXY). In addition, many transcription factors located on autosomes, such as DMRT1 and SOX9, are involved in regulating testicular development. Duplication or deletion of chromosomal segments containing these factors can lead to testicular developmental disorders.