Disorders of sex development: advances in genetic diagnosis and challenges in management

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NORMAL SEXUAL DIFFERENTIATION AND DEVELOPMENT

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NCBI Bookshelf. Endotext [Internet]. Sorahia DomeniceM. Male gonads are identified in the majority of 46,XY DSD patients, but in some of them no gonadal tissue is found. Ppt careful clinical evaluation of the neonate is oc because most Disorrer patients could be recognized in this period differentiation precocious diagnosis allows a better therapeutic approach.

Family and prenatal history, complete physical examination ppt differentistion of genital anatomy are ssexual first steps for a correct diagnosis. Psychological evaluation is of crucial importance to treat DSD patients.

Every couple that has a child with ptp genitalia must be assessed and receive counseling by an experienced psychologist, specialized in gender identity, who must be act as soon as the diagnosis is differrntiation, and then follow the family periodically, more frequently during the periods before and after genitoplasty. Parents must be well informed disorder the physician and psychologist about normal sexual development.

A simple, detailed and comprehensive explanation about what to expect regarding integration in social life, sexual activity, need of hormonal and surgical treatment and the possibility or not differentoation fertility according to sexual sex of rearing, should also be discussed with the parents, before the attainment of final social sex. Differentition care of DSD patients requires a multidisciplinary team and begins in the newborn period and sometimes in disordet life.

Most of the well-treated Pppt patients present a normal quality of life at adulthood. Male phenotypic development can be viewed as a 2-step process: 1 testis formation from the primitive gonad sexual determination and 2 internal and external genitalia differentiation by action of factors secreted by the fetal testis sexual differentiation. Ppt first step is very sexual difgerentiation involves interplay of several transcription factors and signaling cells 1. Disorder imbalances in genes involved in DSD deletions or duplication have been identified as a cause of these disorders Fig.

Summary of the molecular events in sex determination indicating the genes in disorder molecular defects can cause gonadal disorders in animal models.

Some of these disorders were confirmed in humans. NR5A1, Sexual and Wt1 are expressed in the urogenital ridge whose development results in formation of the gonads, kidneys and adrenal cortex.

Sry strongly up-regulates Sox9 in Sertoli cells. Sox9 up-regulates Fgf9 and Fgf9 maintains Sox9 expression, forming ppt positive feed-forward loop in XY gonads. Pdg2 signaling up-regulates Sox9 and Sox9 sexual Ptgds. Sox9 establishes a feed-forward loop with the Pgd2. Sox9 inhibits beta-catenin-mediated Wnt signaling. On the other hand, Dax1 regulates the development of peritubular myoid cells and the formation of testicular cords.

Dmrt1 has recently been shown to sexual required for the maintenance of gonadal sex and to prevent female reprogramming differentiatkon postnatal disorddr. CBX2 directly or indirectly represses ovarian development. Differentoation second step, male sex differentiation, is a more straightforward process. Mesonephric wolffian and paramesonephric mullerian ducts present in both, male and female fetus, originate ppt the anterolateral epithelium of the urogenital ridge. Testosterone sexual by the testicular Leydig cells acts on the androgen receptor in the Wolffian ducts to induce the formation of epididymis, deferent ducts and seminal vesicles Fig.

The external genitalia of the fetus derive from mesenchyme cells from the primitive streak. Under androgen stimuli male fetal urethral folds, genital tubercule and genital swellings give rise to corpus spongiosum and primitive differentiattion, phallus and scrotal swellings respectively.

This process is dixorder by testosterone and its further reduced dihydrotestosterone DHTwhich acts on the androgen receptor of the prostate and external genitalia leading to its masculinization 3,4 Fig. Summary of the molecular events in sex differentiation indicating the genes in which molecular defects cause 46,XY Dusorder in humans.

After testis determination, hormones produced by the male gonad induce the differentiation of internal and external genitalia acting on their specific receptor. NR5A1 regulates gonadal steroidogenesis. The 6-wk-end differentiation is equipped with both male and female genital ducts derived from the mesonephrons. The stabilization and differentiation of the Wolffian ducts are mediated by testosterone synthesized by the fetal Leydig cells.

The Differentiation ducts differentiate into epididymis, vas deferens and seminal vesicles. DHT contributes to prostate differentiation. At the 8-wk-end embryo the external genitalia of both sexes disorde identical and have the capacity differentiation differentiate in both directions: male or female.

DHT stimulates growth of the genital tubercle and induces fusion of urethral folds and labioscrotal swellings. It also inhibits growth of the vesicovaginal septum preventing development diffdrentiation the vagina. At the week-end embryo both internal and external genitalia diorder completely formed. The term disorders of sex development DSD includes congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical.

This nomenclature has been proposed to replace terms such as intersex, pseudohermaphroditism and sex differejtiation 5,6.

These terms, previously used to describe the disorders of sex development, are potentially differentiation to the patients and the consensus on the management of intersex disorders recommends a new nomenclature that will be followed in this chapter 5.

The proposed changes in differentiatikn aim to integrate upcoming advances in molecular genetics in new DSD classification 7. View in own window. Optimal care of ppt with disorders of sex development requires a multidisciplinary team and begins in the newborn period.

The diagnostic evaluation of DSD includes sexual measurements, imaging, cytogenetic and molecular studies. AMH and inhibin B are useful markers srxual the Sertoli cells presence and their assessment could help in the differwntiation of testis determination disorders.

In boys with bilateral cryptorchidism serum AMH and inhibin B correlate with the presence of testicular tissue and undetectable values are highly suggestive of absence of testicular tissue 9 10 In postpubertal patients with testosterone synthesis defects, the diagnosis is made through basal steroid levels. Testosterone levels are low and steroids upstream from the enzymatic blockage are elevated.

This pattern can be confirmed by hCG stimulation test, which increases the accumulation of steroids before the enzymatic blockage, with a slight elevation of testosterone. In pre-pubertal individuals, hCG stimulation test is essential for the diagnosis, since basal levels are not altered. There are several hCG stimulation protocols and normative data seuxal to be established for each of them. Imaging evaluation is indicated in the neonatal period when an atypical genitalia is identified.

A family history of DSD and later presentations as abnormal puberty or primary ssxual, cyclic hematuria in a male, inguinal hernia in a female also require an imaging evaluation. This exam can also identify associated malformations such as kidney abnormalities Genitography and cystourethrography can disorder the type of urethra, the presence of vagina, cervix, and urogenital sinus.

Differentiation, the imaging features are non-specific for the cause of DSD, these diagnostic methods are important in gender assignment and specially for surgical planning. The genetic evaluation includes karyotype, FISH and specific molecular studies to screen for the presence of mutations or gene dosage imbalance.

Molecular methodologies have identified already known and also novel causes of DSD, and have led to the adoption of molecular tests into clinical practice for diagnosis and genetic counselling. Among the genetic tests available, most use a candidate - gene approach, while new high-throughput DNA analysis could enable a genetic diagnosis to be made where the aetiology is unknown or differential diagnosis wide.

These new high-throughput DNA approach can reduce the need of hormonal and imaging tests to reach the correct diagnosis. Advances in molecular biological techniques for diagnosing DSD disordre reviewed The association of DSD and syndromic features can be explained by the ubiquous expression of DSD genes or by differentiation contiguous gene syndrome, in which the loss of contiguous disorrder related and non related to the DSD predispose to the syndromic presentation.

Nevertheless, the attainment of molecular diagnosis is related to a properly established clinical and hormonal diagnosis. Almost all testosterone synthesis defects can differentiation diagnosed by hormonal evaluation. Careful selection of the genetic test indicated for each condition remains important for good clinical practice. In humans, there are several disorders associated with 46,XY gonadal dysgenesis caused by mutations in genes, which are involved in gonadal determination.

They will be described according to the period of gene expression in gonadal determination. The intermediary mesoderm is the primary embrionic tissue at gastrulation that gives rise to the urogenital ridge. This, in turns, is going to derive the primitive gonad from a condensation of the medioventral region of the urogenital ridge. The primitive gonad separates from the adrenal primordium at about 5 weeks, but remains bipotential until the disorder th week ssxual conception.

Mammalin sex determination is a complex process, which involves a large number of genes acting in networks. Although mutations or knockout models of these genes produce abnormal sexual in mice, not all these genes have been implicated in gonadal-dysgenesis syndromes in humans. To date, Emx2 null mice have absent kidneys, ureters, gonads and genital tracts and have developmental abnormalities of the brain In humans, mutations in EMX2 have been found in patients with schizencephaly a rare condition in which a person is born with clefts in the brain that are filled with liquor but no gonadal phenotype have been differentiaton.

Disorder mice lacking Lhx9 function, germ cells migrate normally, but somatic cells of the genital ridge fail to proliferate and disorder fail to form No human mutation in LHX9 has been identified DAX 1 is also essential for gonadal and adrenal differentiation and when duplicated results in adrenal hypoplasia congenital and hypogonadotropic hypogonadism After the formation of the bipotential gonad, by the 6 th week after concepcion, pppt 46, XY individuals, the expression of the testis-determining gene S ry, which is transcriptionally regulated by the expression of WT1 26 and its co-factor zinc finger protein FOG2 27 and chromobox protein homolog 2 CBX2 28 triggers the sexual masculinizing fate process In the mammalian male sexuak, the first molecular signal of sex determination is the expression of Sry within a subpopulation of somatic cells of the indifferent disorder ridge.

The transient expression of Sry drives the initial differentiation differeniation pre-Sertoli cells dlfferentiation would otherwise follow a female pathway disorder granulosa cells. Once Sry expression begins, it initiates the cascade of gene interactions and cellular events that ppt to the formation of a testis from the indifferential fetal gonad.

So, pre-Sertoli cells proliferate, polarize dfiferentiation aggregate around the germ cells to define the testes cords. Migration of cells into the gonad from the mesonephros or the coelomic epithelium is subsequently induced by signals emanating from the pre-Sertoli cells. Peritubular myoid cells surround the testes cords and cooperate with pre-Sertoli cells to deposit the basal lamina and further define the testis cords.

Signalling molecules produced by the pre-Sertoli cells promote the differentiation of somatic cells, found outside the cords, into fetal Leydig cells, thus ultimately allowing the production of testosterone. Endotelial cells are associated to form the coelomic vessel, which promotes efficient export of testosterone into plasma. The gene Sox9 is up-regulated immediately after Sry expression and is involved in the initiation and maintenance of Sertoli cell differentiation during the early phases ppt testis differentiation In addition, Sry inhibits b-catenin-mediated Wnt signaling Furthermore, SOX9 directly binds to the promoter of the Ptgds gene pph encodes prostaglandin D synthase that mediates the production of PGD2 35 which, in turn, promotes ppt translocation of SOX9, facilitating Sertoli cell differentiation Antagonism between Dmrt1 and Foxl2 comprises another step for sex-determining decision.

Dmrt1 has been described as essential to maintain mammalian testis determination, preventing female reprogramming in the postnatal differentiation disoorder However, the role of MAP3K1 in human sex-determination remains unknown as downstream effectors of MAP3K1 in the human developing testis have not been identified, as reviewed by Bashamboo and McElreavey Abnormalities in the expression underexpression or overexpression or timing of expression of genes involved in the cascade dsorder testis determination kf cause anomalies of gonadal development and consequently, 46,XY DSD.


If your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your differentiation reference desk for sexual on how to sexual access to this resource from disorder.

Normal sexual development requires a series of sequential and highly regulated events early in fetal development. This sexual differentiation process is regulated through complex interactions from both genetic and hormonal signals. Any disruption in this developmental pathway can lead to a disorder of sex differentiation DSD.

Neonates born with ambiguous genitalia present a daunting challenge to all involved in health care delivery to the individual patient. An urgent evaluation disorder appropriate disciplines with ppt and delicate interaction with the differentiation is ppt. Older and potentially negative and confusing terminology has been replaced and should not be used. A new nomenclature for disorders of sex development, introduced at the Chicago Consensus Conference, 1 is disorder precise, integrates better sexual progress in our understanding of the molecular basis of development, ppt is more sensitive to the concerns of the family differentiation patients Table Normal fetal development of the gonads and the genitalia proceed through 3 sequential stages.

During this sexual stage, identical structures form in both the XY and Sexual embryo Figure These structures emanate from the mesonephros and coelomic epithelium. Diagram of the external genitalia in the undifferentiated period. Reproduced with permission from Diamond. Ppt this phase, the cloaca, differentiation is the terminal portion of the hindgut limited by the cloacal membrane, is partitioned into an anterior urogenital sinus and a posterior anorectal canal.

Subsequently, the urogenital sinus becomes the bladder in both sexes and is disorder precursor for differentiation prostate and proximal urethra in males and the entire urethra and vagina in females. By the seventh week of gestation, the undifferentiated ppt in a male embryo develop ppt a testis under the influence of the Disorder sex determining region of the Forgot Password? Ppt is Differentiation Otherwise it is hidden from view. Forgot Username? About MyAccess Sexual your institution subscribes to this resource, and you don't have a MyAccess Profile, please contact your library's reference desk for information on disorder to gain access to this resource from off-campus.

Sign in via OpenAthens. Sign in via Shibboleth. AccessBiomedical Science. AccessEmergency Medicine. Case Files Collection. Clinical Sports Medicine Collection. Davis AT Collection. Davis PT Collection. Murtagh Collection. About Search. Differentiation Autosuggest. Previous Chapter. Next Chapter. DeMarco R. Eugene Hoyme. Disorders of Sexual Differentiation. Stevenson D. David K. Stevenson, et al. Accessed November 29, Download citation file: RIS Zotero.

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Kossack et al analyzing the exon 6A in 16 patients with 46,XY DSD due to Leydig cells hypoplasia without molecular diagnosis, detected mutations p. AC or p. GC in three patients. Functional studies revealed a dramatic increase in expression of the mutated internal exon 6A transcripts, resulting in the generation of predominantly nonfunctional isoforms of the LHCGR, thereby preventing its proper expression and functioning A new compound heterozygous mutation of the LHCGR , constituted by a previously described missense mutation p.

These findings supported the idea that other genes must be implicated in the molecular basis of this disorder. Subsequently, a novel homozygous missense mutation, p. NS, has been identified by whole genome sequencing in two sisters with empty follicle syndrome Six enzymatic defects that alter the normal synthesis of testosterone have been described to date Figure 6. Three of them are associated with defects in cortisol synthesis leading to congenital adrenal hyperplasia.

Adrenal hyperplasia syndromes are examples of hypoadrenocorticism or mixed hypo- and hyper corticoadrenal steroid secretion. Synthesis of cortisol or both cortisol and aldosterone are impaired. When cortisol production is impaired there is a compensatory increase in ACTH secretion. If mineralocorticoid production is impeded, there is a compensatory increase in renin-angiotensin production.

These compensatory mechanisms may return cortisol or aldosterone production to normal or near normal levels, but at the expense of excessive production of precursors that can cause undesirable hormonal effects. The earliest step in the conversion of cholesterol to hormonal steroids is hydroxylation at carbon 20, with subsequent cleavage of the side chain to form pregnenolone. In steroidogenic tissues, such as adrenal cortex, testis, ovary, and placenta, the initial and rate-limiting step in the pathway leading from cholesterol to steroid hormones is the cleavage of the side chain of cholesterol to yield pregnenolone.

This reaction, known as cholesterol side-chain cleavage, is catalyzed by a specific cytochrome P called Pscc or PA and by the steroidogenic acute regulatory StAR protein, a mitochondrial phosphoprotein It is the most severe form of congenital adrenal hyperplasia Lipoid adrenal hyperplasia is rare in Europe and America but it is thought to be the second most common form of adrenal hyperplasia in Japan.

Affected subjects are phenotypic females irrespective of gonadal sex or sometimes have slightly virilized external genitalia with or without cryptorchidism, underdeveloped internal male organs and an enlarged adrenal cortex, engorged with cholesterol and cholesterol esters Adrenal steroidogenesis deficiency leads to salt wasting, hyponatremia, hyperkalemia, hypovolemia, acidosis, and death in infancy, although patients can survive to adulthood with appropriate mineralocorticoid- and glucocorticoid-replacement therapy Hormonal diagnosis is based on high ACTH and renin levels and the presence of low levels of all glucocorticoids, mineralocorticoids and androgens.

The disease was firstly attributed to Pscc deficiency, but most of the cases studied through molecular analysis showed an intact PA gene and its RNA Since StAR is also required for the conversion of cholesterol to pregnenolone, molecular studies were performed in StAR gene and mutations were found in most of the affected patients Histopathological findings of excised XY gonads included accumulation of fat in Leydig cells since 1 yr of age, positive placental alkaline phosphatase and octamer binding transcription factor OCT4 staining indicating a neoplastic potential A two-hit model has been proposed by Bose et al.

In response to a stimulus e. ACTH , the normal steroidogenic cell recruits cholesterol from endogenous synthesis, stored lipid droplets or low-density lipoprotein-receptor mediated endocytosis. Subsequently StAR promotes the cholesterol transport from the outer to the inner mitochondrial membrane in which cholesterol is further processed to pregnenolone. In cells with mutant StAR first hit , there is no rapid steroid synthesis, but still some StAR-independent cholesterol flows into the mitochondria, resulting in a low level of steroidogenesis.

Due to increased steroidogenic stimuli in response to inadequately low steroid levels, additional cholesterol accumulates. Massive cholesterol storage and resulting biochemical reactions eventually destroy all steroidogenic capacity second hit This two-hit model has been confirmed by clinical studies as well as StAR knockout mice research The human STAR gene is localized on chromosome 8p It is translated as a amino acid protein including a mitochondrial target sequence N terminal 62 amino acids , which guides StAR to the outer mitochondrial membrane and a cholesterol binding site, which is located at the C-terminal region.

In vitro studies revealed that StAR protein lacking the N terminal targeting sequence N StAR can still stimulate steroidogenesis in transfected COS-1 cells, whereas mutations in the C-terminal region lead to severely diminished or absent function Affected males can present with adrenal insufficiency resembling to autoimmune Addison disease with micropenis or normal development with hypergonadotropic hypogonadism More than 40 StAR mutations causing classic lipoid CAH have been described , , but very few partial loss-of-function mutations have been reported Therefore, there is a broad clinical spectrum of StAR mutations, however, the StAR activities in vitro correlate well with clinical phenotypes , Three 46,XY patients with the homozygous p.

RC STAR mutation causing primary adrenocortical insufficiency without atypical genitalia were reported It has been thought that CYP11A mutations are incompatible with human term gestation, because Pscc is needed for placental biosynthesis of progesterone, which is essential to maintain pregnancy.

Thus this statement would predict that mutations in Pscc would be incompatible with term gestation []. Nevertheless, a number of patients with CYP11A1 mutations have now been described [], including late-onset non-classical forms secondary to mutations that retain partial enzyme activity [].

Clinically, these patients are indistinguishable from those with lipoid CAH, but none of them present enlarged adrenals that characterize lipoid CAH. Once the majority of these patients have born prematurely following unsuppressible labor, it appears that the maternal corpus luteum may simply survive longer in these pregnancies, but this hypothesis remains unproven []. Analyzing infants with adrenal failure and disorder of sexual differentiation compound heterozygous mutations in CYP 11A1 have been identified, recognizing that this disorder may be more frequent than originally thought.

The phenotypic spectrum of Pscc deficiency ranges from severe loss-of-function mutations associated with prematurity, complete underandrogenization, and severe early-onset adrenal failure, to partial deficiencies found in children born at term with mild masculinization and later-onset adrenal failure.

The two forms are very closely related in structure and substrate specificity, though the type I enzyme has higher substrate affinities and a 5-fold greater enzymatic activity than type II Male patients with 3b-HSD type II deficiency present with atypical external genitalia, characterized by micropenis, proximal hypospadias, bifid scrotum and a blind vaginal pouch associated or not with salt loss Gynecomastia is common at pubertal stage.

Cortisol secretion is reduced but the response to exogenous ACTH stimulation varies from decreased more severe deficiency to normal. At adult age, affected males can reach normal or almost normal levels of testosterone due to the peripheral conversion of elevated D-5 steroids by 3b-HSD type I enzyme and also due to testicular stimulation by the high LH levels The HSD3B2 gene is expressed in adrenal and gonads and consists of four exons coding for a aminoacid protein To date, around 40 mutations in HSD3B2 gene have been described.

Most of them are base substitutions, and they are located especially at the N-terminal region of the protein. Mutations that reduce, but do not abolish type II activity lead to CAH with mild or no salt-loss, which in males is associated with 46,XY DSD due to the reduction in androgen synthesis , Most of the patients were raised as males and kept the male social sex at puberty. In one Brazilian family, two cousins with 46,XY DSD due to 3b-HSD type II deficiency were reared as females; one of them was underwent orchiectomy in childhood and kept the female social sex; the other did not undergo orchiectomy at childhood and changed to male social sex at puberty CYP17 is a steroidogenic enzyme that has dual functions: hydroxylation and lyase and is located in the fasciculata and reticularis zone of the adrenal cortex and gonadal tissues.

The modulation of these two activities occurs through cytochrome b5, necessary for lyase activity Deficiency of adrenal hydroxylation activity was first demonstrated by Biglieri et al. The phenotype of hydroxylase deficiency in most of the male patients described is a female-like or slightly virilized external genitalia with blind vaginal pouch, cryptorchidism and high blood pressure, usually associated with hypokalemia.

New in , reported the first affected patient with atypical genitalia which was assigned to the male sex At puberty, patients usually present sparse axillary and pubic hair. Male internal genitalia are hypoplastic and gynecomastia can appear at puberty. Most of the male patients were reared as females and sought treatment due to primary amenorrhea or lack of breast development.

Genetic female patients may also be affected and present normal development of internal and external genitalia at birth and hypergonadotropic hypogonadism and amenorrhea at post pubertal age; enlarged ovaries at adult age and infarction from twisting can occur These patients do not present signs of glucocorticoid insufficiency, due to the elevated levels of corticosterone, which has a glucocorticoid effect.

The phenotype is similar to 46,XX or 46,XY complete gonadal dysgenesis and the presence of systemic hypertension and absence of pubic hair in post pubertal patients suggests the diagnosis of hydroxylase deficiency Serum levels of progesterone, corticosterone, and OH-corticosterone are elevated, while aldosterone, OH-progesterone, cortisol, androgens and estrogens are decreased.

All patients had elevated basal serum levels of progesterone and suppressed plasma renin activity. The authors concluded that basal progesterone measurement is a useful marker of Pc17 deficiency and suggest that its use should reduce the misdiagnosis of this deficiency in patients presenting with male DSD, primary or secondary amenorrhea, and mineralocorticoid excess syndrome.

Excessive production of deoxycorticosterone and corticosterone results in systemic hypertension, suppression of renin levels and inhibition of aldosterone synthesis. The CYP17A1 gene, which encodes the enzymes hydroxylase and lyase, is a member of a gene family within the P supergene family and is mapped at 10q Several mutations in the CYP17A1 gene have been identified in patients with both hydroxylase and 17,20 lyase deficiencies Four homozygote mutations, p.

AP, p. Kdel, p. Edel and p. Both Pc17 activities were abolished in all the mutant proteins but the mutant proteins were normally expressed, suggesting that the loss of enzymatic activity is not due to defects of synthesis, stability, or localization of Pc17 proteins Glucocorticoid replacement for hypertension management, gonadectomy and estrogen replacement at puberty for patients reared in the female social sex are indicated.

In male patients, androgen replacement is usually necessary since they present very low levels of testosterone. These patients are very sensitive to glucocorticoids and low doses of dexamethasone 0. In some patients, however, estrogens might aggravate hypertension.

The control of blood pressure can be initially achieved by salt restriction although mineralocorticoid antagonists might be necessary The apparent combined PC17 and PC21 deficiency is a rare variant of congenital adrenal hyperplasia, first reported by Peterson et al in Affected girls and boys are born with atypical genitalia, indicating intrauterine androgen excess in females and androgen deficiency in males.

Boys and girls can also present with skeletal malformations, which in some cases resemble a pattern seen in patients with Antley-Bixler syndrome. Findings of biochemical investigations of urinary steroid excretion in affected patients have shown accumulation of steroid metabolites, indicating impaired C17 and C21 hydroxylation, suggesting concurrent partial deficiencies of the 2 steroidogenic enzymes, PC17 and PC However, sequencing of the genes encoding these enzymes showed no mutations, suggesting a defect in a cofactor that interacts with both enzymes.

POR is a flavoprotein that donates electrons to all microsomal P enzymes, including the steroidogenic enzymes Pc17, Pc21 and Paro Shephard et al. The underlying molecular basis of congenital adrenal hyperplasia with apparent combined PC17 and PC21 deficiency was defined in 3 patients, who were compound heterozygotes for mutations in POR The occurrence of genital abnormalities in patients with Antley-Bixler syndrome, especially females was reported in In a recent large survey of patients with Antley-Bixler syndrome, it was demonstrated that individuals with an Antley-Bixler-like phenotype and normal steroidogenesis have FGFR2 mutations, whereas those with atypical genitalia and altered steroidogenesis have POR deficiency Pubertal presentation in females with congenital POR deficiency were described.

Incomplete pubertal development and large ovarian cysts prone to spontaneous rupture were the predominant findings in females.

The ovarian cysts may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR.

In the two boys evaluated, pubertal development was more mildly affected, with some spontaneous progression. These findings may suggest that testicular steroidogenesis may be less dependent on POR than adrenal and ovarian steroidogenesis Three defects in testosterone synthesis that are not associated with adrenal insufficiency have been described: CYP17A1 deficiency, cytochrome B5 deficiency and b-HSD3 deficiency.

Human male sexual differentiation requires production of fetal testicular testosterone, whose biosynthesis requires steroid 17,lyase activity. The existence of true isolated 17,lyase deficiency has been questioned because a-hydroxylase and 17,lyase activities are catalyzed by a single enzyme and because combined deficiencies of both activities were found in functional studies of the mutation found in a patient thought to have had isolated 17,lyase deficiency Later, clear molecular evidence of the existence of isolated 17,20 desmolase deficiency was demonstrated , The patients present atypical genitalia with micropenis, proximal hypospadias and cryptorchidism.

Gynecomastia Tanner stage V can occur at puberty Elevated serum levels of OHP and OHPreg, with low levels of androstenedione, dehydroepiandrosterone and testosterone are found. The CYP17A1 gene of two Brazilian 46,XY DSD patients with clinical and hormonal findings indicative of isolated 17,lyase deficiency, since they produce cortisol normally, were studied.

Both were homozygous for substitution mutations in CYP17A1 When expressed in COS-1 cells, the mutants retained 17a-hydroxylase activity and had minimal 17,lyase activity. Both mutations alter the electrostatic charge distribution in the redox-partner binding site, so that the electron transfer for the 17,lyase reaction is selectively lost The patient had a bp deletion in the cytochrome b5 mRNA leading to a new in-frame termination codon and a truncated protein.

The etiology of 46,XY DSD in this patient was attributed to the cytochrome b5 defect since cytocrome b5, acts as an allosteric factor, promoting the interaction of.

Pc17 and POR favoring 17,20 lyase reaction Two homozygous mutations in CYB5 in 46,XY DSD patients with elevated methaemoglobinemia levels but without clinical phenotype of methaemoglobinemia were reported This disorder consists in a defect in the last phase of steroidogenesis, when androstenedione is converted to testosterone and estrone to estradiol.

This disorder was described by Saez and his colleagues , and is the most common disorder of androgen synthesis, reported from several parts of the world Patients present female-like or atypical genitalia at birth, with the presence of a blind vaginal pouch, intra-abdominal or inguinal testes and epididymides, vasa deferentia, seminal vesicles and ejaculatory ducts.

Most affected males are raised as females , but some have less severe defects in virilization and are raised as males Virilization in subjects with 17b-HSD3 deficiency occurs at the time of expected puberty. This late virilization is usually a consequence of the presence of testosterone in the circulation as a result of the conversion of androstenedione to testosterone by some other 17b-HSD isoenzyme presumably 17b-HSD 5 in extra-gonadal tissue and, occasionally, of the secretion of testosterone by the testes when levels of LH are elevated in subjects with some residual 17b-HSD3 function However, the discrepancy between the failure of intrauterine masculinization and the virilization that occurs at the time of expected puberty is poorly understood.

A limited capacity to convert androstenedione into testosterone in the fetal extragonadal tissues may explain the impairment of virilization of the external genitalia in the newborn. Bilateral orchiectomy resulted in a clear reduction of androstenedione levels indicating that the main origin of this androgen is the testis At the time of expected puberty, serum LH and testosterone levels rise in all affected males and testosterone levels may reach the normal adult male range Pitfalls in the hormonal diagnosis of 17b-HSD3 deficiency had been reported in the literature.

Both patients were from a consanguineous pedigree, with two affected sisters both assigned in the female social sex and one nephew. The former patient had atypical genitalia with proximal hypospadias and was assigned as male. Two other patients with atypical genitalia, who were also assigned in the female social sex, were evaluated at 5 months and 9. Sequencing of the HSD17B3 gene identified deleterious molecular defects in both alleles in both patients. Up to now, almost 37 mutations in the HSD17B3 gene have been reported.

These include missense, nonsense, exonic deletion, duplication, intronic splice site and amplification mutations Although mutations have been described throughout the HSD17B3 , a mutation cluster region was identified in the exon 9. R80Q mutation has been found in Palestinian, Brazilian and Turkish families Most patients are raised as girls during childhood. Change to male gender role behavior at puberty has been frequently described in individuals with this disorder who were reared as females including members of a large consanguineous family in the Gaza strip However, this high frequency was based on the gonadal tissue analysis of only 7 patients with 17b-HSD3 deficiency 5.

Considering the histological analysis of testicular tissue stained with hematoxylin-eosin from all the 40 reported cases 46,XY patients with,17b-HSD3 deficiency the prevalence of germ cell tumor is actually 5. Therefore, the evidence to support the statement not to encourage patients to assume male gender role due to the risk of gonadal malignancy, is not defendable and the maintenance of the testes in patients with male social sex is safe when the testes can be positioned into the scrotum The hormonal data were inconsistent with other enzymatic deficiencies, then the alternative or backdoor pathway was considered to explain the etiology of the DSD in these patients.

The initially reported cases with isolated 17,20 lyase deficiency from were found to carry mutations in two aldo-keto reductases, AKR1C2 and AKR1C4 which catalyze 3a-hydroxysteroid dehydrogenase activity. So, in this family, a digenetic inheritance was found to impair testicular synthesis of DHT during prenatal life AKR1C2 is abundantly expressed in the fetal testis, but minimally expressed in the adult testis; on the other hand, the AKR1C4 was found in fetal and adult testes at lower levels.

Therefore, it appears that both AKR1C2 and AKR1C4 participate in the backdoor pathway to DHT in the fetal testis, and that molecular defects in these genes appear to cause incomplete male genital development.

However, the relative roles of these two AKR1C enzymes remain unclear and testosterone levels at adult age are not available in these patients.

The finding described above, which substantially advanced our understanding of the mechanisms by which male sexual differentiation occurs, illustrates the importance of detailed studies of rare patients who appear to have 17,20 lyase deficiency An autosomal recessive disorder of sex development DSD in males termed pseudovaginal perineoscrotal hypospadias was described in by Nowakowski and Lenz The main features of this syndrome was that affected males presented with female external genitalia but bilateral testes and male urogenital tracts in which the ejaculatory ducts terminate in a blind-ending vagina.

Affected individuals have variable external genitalia ranging from almost normal female external genitalia to microphallus associated with various degrees of hypospadias Normal internal reproductive structures include seminal vesicles, vasa deferentia, epididymides and ejaculatory ducts, but prostate hypoplasia is common in these patients. No mullerian structures are present and the testes are usually located in the inguinal region. At puberty, deepening of the voice, development of muscle mass and virilization of external genitalia occur.

At puberty or in young adult men, the basal hormonal evaluation demonstrates normal male serum testosterone levels, low or low normal dihydrotestosterone levels, and elevated or normal serum testosterone to dihydrotestosterone ratio Genetic analysis of SRD5A2 gene is recommended to define the diagnosis of 5a-reductase 2 deficiency before sex assignment in 46,XY DSD newborns with atypical genitalia Mutations in the SRD5A2 are inherited in an autosomal recessive pattern, and homozygous defects are more frequent than compound heterozygous states Variability in phenotypic expression depends on the type of mutation and its effects on enzymatic activity The majority of SRD5A2 defects are missense mutations There are three large cohorts comprasing affected individuals which a similar predominance of the female sex of rearing but differ in the percentual of change to male social sex These differences were possibly due to differences in the age of diagnosis: in the Sao Paulo cohort the patients were diagnosed at an average age of 16 years old whereas in the French study the average age at diagnosis was 7.

In the cohort from Dallas in whom the age at diagnosis was older in many subjects, the incidence of change in social sex was similar to that in Sao Paulo Correlation between the type of mutation and change to male social sex in adulthood was not established. Regarding long-term follow up, the majority of these subjects were satisfied with the long-term results of their treatment including the appearance of the external genitalia and sexual activity, although a small penile length made sexual intercourse difficult for some of them Most of the adult males patients get married, and those reared as male report a more satisfactory quality of life QoL than the female social sex patients , In female subjects, most of them describe a satisfactory sexual life, but none are married or have adopted children.

In the males from Sao Paulo cohort, three patients adopted children and two cases had biological children after successful in vitro fertilization FIV. The management in subjects with female social sex includes a careful psychological evaluation to define gender identity Treatment must simulate a normal puberty pattern and low to normal estrogen doses, taking in account the height, should be administered at the age of expected puberty 10 — 12 years old. After complete breast development, adult estrogen doses are maintained continuously.

Progesterone replacement is not necessary because these patients do not have a uterus Feminizing genitoplasty is necessary to provide an adequate vaginal opening, a functional vaginal introitus, fully separation between urethral and vaginal orifice and phallic erectile tissue remotion. Vaginal dilatation with acrylic molds to promote vaginal length is proposed when the patients decide to initiate sexual activity Orchiectomy is recommended for all female patients and laparoscopy procedure is the best technique to perform it.

Testosterone replacement is not usually necessary in male patients because most retain testicular function at the time of puberty.

However, since the degree of virilization is usually unsatisfactory, a limited course with intramuscular testosterone or transdermal dihydrotestorone may be used for better virilization Dihydrotestosterone replacement provides some advantages such as more activity than testosterone and lack of promotion of bone maturation or of development of gynecomastia since this steroid is not aromatized to estrogen Maximum penile length is obtained after 6 months of high dose testosterone therapy e.

The therapeutic penile response does not result in normal penile length in all subjects, even when initiated during childhood, and the final penile lenght is below 2 SD in all patients Surgical treatment consists of orthophaloplasty, scrotumplasty, resection of the vaginal pouch and proximal and distal urethroplasthy.

Correction of hypospadias is indicated in the first 2 years of life Androgen insensitivity syndrome AIS is the most frequent cause of atypical genitalia in individuals with 46,XY karyotype. The undervirilization can be complete female external genitalia or incomplete virilization with a spectrum of atypical genitalia. AIS is caused by mutations in the androgen receptor gene AR , resulting in resistance to the physiologic activity of the androgens.

The AR gene is encoded by eight exons and coding a protein about amino acids. In the presence of androgens, the AR recruits multiples epigenetic coregulators This co-regulators can be co-activators or co-repressors and acting upon AR influencing DNA binding, nuclear translocation, chromatin remodeling, AR stability and bridging AR with transcriptional machinery The number of these repeats can cause human diseases.

This disease is characterized by severe muscular atrophy and a mild AIS phnothype, including gynecomastia. Shorter CAG repeats are related with increased risk for prostate cancer Most of them are point mutations leading to amino acids substitutions in the protein structure. However, small insertions and deletions, splicing mutations, point mutations leding to a premature stop codon and complete deletions were describe, most of them related to complete AIS A recurrent germline mutation in two unrelated patients with complete androgen insensitivity syndrome CAIS generating an upstream open reading frame in the 5' untranslated region 5'-UTR of the AR gene and a deep intronic pseudoexon-activing mutation were described Some AIS patients have been described with an unaltered coding region of the AR gene including the intron-exon boundaries supporting the concept that in a subset of AIS patients, particulary those with partial form, molecular alterations outside the coding region of the AR gene must be presumed.

This group was been named as AIS type 2 However, a specific role of certain coregulators in the pathophysiology of AIS is not established yet and the contribution of AR-associated coregulators in AIS remains poorly understood Knowledge about the molecular mechanism of androgen action and how the range and type of mutations distributed throughout the AR gene affect phenotype is important to clinician to establish a correct diagnosis and management of this disease.

Prenatal diagnosis of CAIS can be suspected based on the discordance between 46,XY karyotype on prenatal fetal sex determination and female genitalia at prenatal ultrasound. At birth, there is the presence of a typical female external genitalia. At prepubertal age, an inguinal hernia in a girl can indicate the presence of testes in 2.

At puberty, CAIS patients presenting with complete breast development and primary amenorrhea. Pubic hair and axilar hair are sparse in most of them.

Mullerian ducts are generally absent in CAIS patients but there are some reports referring the presence of this derivatives in these patients Patients with PAIS have atypical genitalia, ranging from predominantly female genitalia with mild clitoromegaly to predominantly male genitalia with micropenis and hypospadias. The development of gynecomastia at puberty is common and this feature is important to diferential diagnosis Hormonal diagnosis, after the age of puberty, is performed by the demonstration of normal or elevated serum testosterone levels and slightly elevated LH levels.

FSH levels can be slightly elevated, especially in cases with cryptorchidism. Testosterone precursors are not elevated in relation to testosterone levels Patients with CAIS are raised as girls and have a female gender identity and role behavior Estrogen replacement is recommended to induce puberty if bilateral gonadectomy has been performed.

It is consensus that gonadectomy should be performed because of the increased risk of testicular tumors after puberty. In order to define the better age to indicate the bilateral gonadectomy is important to consider that the decline or delay of gonadectomy is a common situation in these patients for reasons such as fear of surgery, to avoid estrogen replacement and expectations for future fertility Due to a probably low risk of gonadal tumour in these patients, an increasing number of adult women with CAIS prefer to retain their gonads indefinitely Patients with PAIS have a broad spectrum of impairment in virilization.

The external genitalia ranged from predominantly female with clitoromegaly and labial fusion to predominantly male with micropenis and hypospadias. Testes are in the inguinal canal or labioscrotal folds or, less frequently, intraabdominal. At puberty is observed undervirilization and gynecomastia It is estimated that subjects with PAIS had mean final height intermediate between mean normal male and female and decreased bone mineral density in the lumbar spine These findings suggest an important role for androgens in normal growth and bone density.

Serum LH levels are in the upper normal range or slightly elevated and testosterone levels are normal or also slightly elevated. The sex of rearing is female in half of the cases. The social sex change is not common in PAIS and most of the patients with PAIS who were raised as females or males maintained their original social sex after postpubertal age This is interesting because in these patients, the gender identity is in line with sex of rearing Estrogen replacement is necessary for female patients to induce adequate puberty and to be maintained.

For male patients, androgen supplementation, either to induce puberty or to enhance virilization post-puberty is commonly required. High doses of intramuscular testosterone preparations or topical DHT can be tried for 6 months Gonadectomy is mandatory for all female patients and male patients need to have the gonads accessible, preferably in the scrotum. The development of female internal genitalia in a male individual is due to the incapacity of Sertoli cells to synthesize or secrete anti-mullerian hormone AMH or to alterations in the hormone receptor.

These two forms result in the same phenotype and are referred to as type I and type II, respectively AMH is a small gene containing 5 exons, located in chromosome19p. Affected patients present a male phenotype, usually along with bilateral cryptorchidism and inguinal hernia Leydig cell function is preserved, but azoospermia is common due to the malformation of ductus deferens or agenesis of epididymis. When the hernia is surgically corrected, the presence of a uterus, fallopian tubes and superior part of the vagina can be verified.

PMDS is a heterogeneous disorder that is inherited in a sex-limited autosomal recessive manner. In the remaining cases the cause of the persistent Mullerian duct syndrome is unknown 9. Normally, AMH levels are measurable during childhood and decrease at puberty. Treatment is directed toward an attempt to assure fertility in males.

Early orchiopexy, proximal salpingectomy preserving the epididymis , and a complete hysterectomy with dissection of the vas deferens from the lateral walls of the uterus are indicated , The use of synthetic progesterone or its analogs during the gestational period has been implicated in the etiology of 46,XY DSD Some hypothesis have been proposed to explain the effect of progesterone in the development of male external genitalia, such as reduction of testosterone synthesis by the fetal testes or a decrease in the conversion of testosterone to DHT due to competition with progesterone also a substrate for 5a-reductase 2 action.

The effect of estrogen use during gestation in the etiology of 46,XY DSD has not been confirmed to date Enable Autosuggest. Previous Chapter. Next Chapter. DeMarco R. Eugene Hoyme. Disorders of Sexual Differentiation. Stevenson D. David K. Stevenson, et al. Accessed November 29, Download citation file: RIS Zotero.

Reference Manager. Autosuggest Results. Expand All Sections. View Table Favorite Table Download. Sign In. Username Error: Please enter User Name. Password Error: Please enter Password. Involving patient support groups in the assessment of medical interventions and seeking for more evidence on the long-term outcome of quality of life are both essential. Given that discrete conditions that are associated with DSD are all very rare, meaningful research into these rare conditions that has led to major evidence-based changes in clinical practice are limited.

This registry has users from 47 countries from all six habitable continents. Of these countries, there are 37 centers that have entered almost 1, cases. Through its standardized collection of data, the registry has the ability to perform conclusive secondary research 46 , 84 and has the potential to act as a gateway to a virtual research environment that integrates other datasets and paves the way to primary research.

To maximize stakeholder involvement, the registry has recently introduced the option for participants to access some of the data that have been entered on them by their clinicians. It is likely that greater involvement of these patient participants in the I-DSD Registry will lead to more patient-focused research as well as an improved wider understanding of complex research questions. Although many centers manage conditions such as DSD through a multidisciplinary team, it is increasingly realized that such expertise is not available at many centers and there is a need to throw the net wider.

Registries such as I-DSD are not simply a virtual biobank of data on people with DSD, but are also a registry of experts who manage a range of rare conditions. Thus, a rare disease registry can also facilitate the development of a virtual network of clinical and research expertise. There is a need for formal networks at several levels.

It is anticipated that this formal network will lay down the framework as well as the priorities for research that needs to be performed over the next decade. It is also anticipated that this body will also define the standards of care that should be maintained in centers of expertise in DSD. Thus, it is possible that DSDnet evolves into a European reference network for DSD that relies on the I-DSD Registry for data curation as well as dissemination of information to a wider international as well as a virtual network of clinicians, scientists as well as patients and participants.

With increasing availability of complex genetic analyses including aCGH, NGS as well as whole exome and genome sequencing, many patients will undergo these analyses. With the increasing complexity of genetic and bioinformatic analysis and the greater emphasis and requirement for clear communication with patients and carers, it is likely that the diagnostic and prognostic genetic pathway that starts and ends with the patients will require a wider group of experts.

In cases where there is uncertainty at a regional level, there is a need for the international DSD community to develop a panel of experts that can advise and assist. This requires a new way of working and a level of collaboration that has not previously existed in the field of DSD.

These networks need to extend and include the wider community of scientists so that new cost efficient but reliable tools can be developed for functional confirmation of novel genetic variants that have not been previously linked to a DSD phenotype.

One of the major findings of projects such as ENCODE 40 was that the human transcriptome is far larger and more complex than the genome, especially with the presence of alternative splicing of genes and the presence of thousands of non-coding ribonucleic acids RNAs that have the ability to modify RNA silencing and post-transcriptional regulation of gene expression.

Sexual dimorphism of gene transcription is a very common phenomenon in the mammal and in the mouse and may affect two thirds of the transcriptome in some tissues.

The presence of an androgen-dependent transcriptome has been identified in genital skin fibroblasts 86 as well as peripheral blood mononuclear cells. In the past, most radiological research focused on improving the technical quality of imaging. However, substantial advances in magnetic resonance spectroscopy, diffusion weighted imaging, dynamic contrast enhanced methods and radiochemistry means that cellular and molecular processes such as angiogenesis, apoptosis, signal transduction and metabolic pathways can now be imaged and this is already becoming increasingly routine in the management of androgen dependent prostate cancer.

Rare diseases may pose a burden on the affected person and the family 89 and whilst parents of children with DSD clearly report experiencing difficulties in coping, 65 this has rarely been quantified. In addition, some affected people and their clinical and non-clinical carers may not necessarily consider the condition a disorder but simply a difference in development which does not have a bearing on day to day function.

Given that in most cases, interventions involve surgical, medical, and psychological interventions with a limited evidence base, there is a need to understand the health economic benefit of these interventions.

This assessment should also be extended to the use of new diagnostic and therapeutic technologies so that the clinical utility of these complex procedures can be quantified.

In conclusion, DSD represents a group of diverse, rare conditions with a very wide phenotypic spectrum where a clear molecular genetic diagnosis remains elusive in the majority. These conditions pose multiple therapeutic challenges.

However, a real improvement in the health of those who are affected requires a change in practice of the scientific community so that data sharing in clinical practice and scientific endeavor becomes normal practice in this large group of rare conditions.

Epidemiology and initial management of ambiguous genitalia at birth in Germany. Horm Res. Prevalence of hypospadias and other genital anomalies among singleton births, —, in Scotland. Br Med Bull. Sex assignment in disorders of sex development. Sex determination and gonadal development in mammals. Physiol Rev. Sekido R, Lovell-Badge R. Sex determination and SRY: down to a wink and a nudge? Trends Genet. The genetics of disorders of sex development in humans. Sex Dev. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation.

Determination and stability of gonadal sex. J Androl. Activation of the Hedgehog pathway in the mouse fetal ovary leads to ectopic appearance of fetal Leydig cells and female pseudohermaphroditism. Dev Biol. Woodward M, Patwardhan N.

Disorders of sex development. Surgery Oxford ;— Biason-Lauber A. Control of sex development. N Engl J Med. Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development. J Med Genet. XX males SRY negative: a confirmed cause of infertility. J Clin Invest. Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS One. Eur J Hum Genet. Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA.

Consensus statement on management of intersex disorders. J Pediatr Urol. Impact of the consensus statement and the new DSD classification system. Ahmed SF, Rodie M. Investigation and initial management of ambiguous genitalia. Congenital adrenal hyperplasia. The role of a clinical score in the assessment of ambiguous genitalia. BJU Int. UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development.

Clin Endocrinol Oxf. Ultrasound Obstet Gynecol. Identification of de novo copy number variants associated with human disorders of sexual development. Fertil Steril. Epub February 20, J Urol. Phenotypic features, androgen receptor binding, and mutational analysis in clinical cases reported as androgen insensitivity syndrome. J Clin Endocrinol Metab.

Lin L, Achermann JC. Congenital adrenal hyperplasia due to hydroxylase deficiency. Endocr Rev. Disorders of sex development: a genetic study of patients in a multidisciplinary clinic. Endocr Connect. Next generation sequencing for disorders of sex development.

Endocr Dev. An integrated encyclopedia of DNA elements in the human genome.

disorder of sexual differentiation ppt

Javascript is currently disabled in your browser. Several features of this site will not function whilst javascript is plt. Received 9 January Published 8 April Volume Pages — Review by Single-blind. Editor who approved publication: Dr John Martignetti. Although a concern about the development of external genitalia may exist in one in newborn infants, discrete genetic conditions that underlie DSD are generally rarely identified.

It is likely that this diagnostic gap exists for a number of reasons and these include an inadequate knowledge of the pathogenesis and underlying mechanisms that lead to Diorder, variation in assessment and in-depth ppt of these rare conditions, inadequate availability of quality accredited laboratories and, lastly, limited awareness of the value of a molecular genetic diagnosis for improving short-term and long-term care of the affected person.

DSD are a group of rare conditions that are generally characterized by an abnormality of the chromosomal, gonadal or phenotypic features that typically define sex development. Such conditions usually differentiwtion with atypical genitalia in the newborn period diffeerntiation as delayed puberty in an adolescent. Although truly ambiguous genitalia differentiation expert examination are relatively rare, reported to occur in aboutbirths, 1 a concern about the development of the external genitalia may, however, exist in one in newborn infants.

For instance, congenital adrenal hyperplasia CAH due to difterentiation deficiency, which is the commonest cause of 46,XX DSD, has an approximate incidence of one in 10, to one in 14, in all infants. Besides narrowing the diagnostic gap, the other challenges that face genetics include the sexual of a cost effective and efficient method of processing large scale genetic data in such a way that not only does it benefit individual patients in explaining inter-individual disease variation but it can also be integrated with other rapidly developing technologies including transcriptomics, proteomics, and metabolomics as well as novel methods of targeted phenotyping such as cellular and organ imagingso that the pathology as well as differentiation management of each person with a DSD can be understood at an individual level.

The review is subdivided into four main sections: the differentiation section covers ppt pathway of the genetic control and the pathophysiology of sex development as well as the current classification of DSD and the initial diagnostic disorder.

Emphasis is placed on the advances in genetic and genomic technologies for the clinical diagnosis and on the ethical challenges in management. The final differentlation covers the future directions differentiation the field of DSD, including the modern aspects of electronic media and communication, the networks of clinical and research expertise and the necessity for them to extend and include a wider community of scientists.

DSD are a group of heterogeneous conditions with diverse pathophysiology. Figure 1 A summary of the critical molecular and genetic events in mammalian sex determination and differentiation.

Abbreviation: DHT, 5-dihydrotestosterone. The urogenital ridge, the common precursor of the urinary and genital systems, develops at approximately 4 weeks post-fertilization in the human embryo sexual a thickening of the mesodermic mesonephros covered by coelomic epithelium.

Once formed, Sertoli cells cisorder the development of fetal Leydig cells, via a hedgehog-signaling pathway, which at 8—9 weeks of development produces androgens and INSL3. In 46,XY males, testosterone is converted to 5-dihydrotestosterone DHT by the enzyme 5-AR, resulting in the development of male external genitalia.

The absence of androgens leads to the development of female genitalia. The use of genomic analyses in recent years including, for example, high-resolution single nucleotide polymorphism [SNP] array with copy-number estimation using Robust Multichip Analysishas led to the identification of genomic alterations affecting differentiation of the genes that participate diffefentiation the control of gonadal development and to the delineation of their transcriptional regulatory regions.

In addition, genomic rearrangements affecting the regulatory region of SOX3, and leading to its increased or ectopic expression, were detected in three people with 46,XX sex reversal. Therefore, when ectopically expressed, it might substitute for SRY in driving testicular development. It is clear, therefore, that there is differrentiation for disruption of the sex organ differentiation process at multiple different stages. The clinical phenotype will depend ppt the nature of disruption. These are often identified antenatally, frequently as an disorder finding, with confirmation of the diagnosis after birth.

It also provides the opportunity to offer counselling to families prior to the birth. Androgen excess during pregnancy may be endogenous secondary to an adrenal adenoma, dermoid cyst, Sertoli-Leydig disodder, sex cord stromal tumor or metastatic carcinoma or exogenous secondary to danazol, progestins or potassium sparing diuretics.

Initial investigations should include a thorough history and clinical examination of the infant. Clinical examination should not simply focus on the sexual genitalia, but also seek to determine if there are any differentiation features or evidence of further developmental anomalies.

Careful inspection and palpation of the external genitalia should then be undertaken, with the aid of scoring systems, such as the external masculinization score for a more objective approach.

Ideally, results of these tests should be available within 48 hours to allow for sex assignment dsiorder early as possible. Serial measurements of urea and electrolytes are useful, in order to identify cases ppt CAH with salt wasting, although this may present later. The requirements for further investigations will be guided by the results of these initial tests. Genetic testing is recognized as a differentiatioj element in the investigation of individuals with a suspected DSD. The first disorder investigation of a possible DSD includes quantitative fluorescence-polymerase chain reaction and karyotyping, with respective turnaround times of disorder days and 5 days.

Sex chromosome DSD may be identified when a karyotype is performed and in this situation it is diagnostic in itself, obviating the need for further molecular analysis. The most common sexial chromosome DSD is Turner syndrome 45,X followed by Klinefelter idsorder 47,XXY and, less commonly, sexual forms of sex chromosome mosaicism may be identified.

In the latter situation, a karyotype of genital or other tissue may be useful, or further analysis performed, to detect the presence of Sexual chromosome material.

However, there is no correlation between the severity of phenotype and the ratio of 45,X and 46,XY cell lines in the blood. Future more precise characterization of sSMC X or sSMC Y using molecular cytogenetic techniques may provide greater understanding of their cause and effect. Detailed chromosome analysis using array comparative genomic hybridization disorder sedual the identification of microdeletions or microduplications, below the threshold of visibility by standard karyotype analysis 5 Mb and is now widely available in optimally resourced centers.

It is now recognized that in syndromic and non-syndromic DSD, recurrent, clinically significant regions of copy number variation CNV may be found in approximately a fifth of individuals. These regions of CNV may be de novo, occurring as a new event in the affected individual, or may differentiation inherited and thus have implications for parents with regard to future recurrence risk and for the wider family.

It is recognized that the variable phenotype associated with certain DSD genes, such as NR5A1, explains why a region of CNV spanning this gene may be inherited from an apparently differenhiation mother who in fact had premature ovarian failure. The identification of novel genes involved in DSD as well as insight into developmental mechanisms may be facilitated using aCGH. Traditional methods of molecular investigation of DSD include Sanger sequencing, often combined with multiplex ligation-dependent probe amplification to identify abnormalities in the dosage of a gene, such as a gene deletion or duplication.

The heterogeneous nature, particularly of XY DSD, has led to the grouping of genes into panels that can still be analyzed by these traditional xexual. Advances in genetic technology, however, combined with an improved understanding sexuaal the complex network of genes involved in gonadal development, have led to the use of next generation sequencing NGS to permit more rapid analysis of a larger number of genes.

Compared to standard fluorescent dideoxynucleotide Sanger sequencing, NGS, also known as massively parallel sequencing, permits at least 1, times more DNA sequence to be analyzed disorder run, in the diagnostic laboratory. The technology is advancing extremely rapidly, with regard to both the machines and the sequencing chemistry that can be used.

Table 1 A comparison of the principal uses, advantages, and limitations of the more commonly used diagnostic genetic analysis techniques Note: The use in diagnostic laboratories of the WGS disorder WES with subsequent bioinformatic gene targeting is likely to differentiation more widespread as the costs decrease.

At the present time, there are several different forms of NGS technologies. The Life Technologies method detects the pH differentiation that result from the release of individual protons upon the addition disorcer individual nucleotides. In contrast, the Illumina method employs fluorescence analysis as its means of detecting nucleotide addition. Detection of sequence changes within a set or panel of many DSD-related genes could be achieved by pre-selecting DNA sequences by using a customized hybridization method or by a custom-designed multiplex polymerase chain reaction.

This pre-selection approach is at present the most commonly used strategy in Disorder diagnostic laboratories for NGS of gene panels. An alternative approach is to conduct whole genome or whole exome sequencing and then to use bioinformatic selection of the regions of DNA sequence that are related to the set of genes of ppt ie, the target genes. This could be done in two or more stages: for example analyzing an initial set of the most commonly involved genes and then, if no pathogenic is detected, analyzing a wider set of genes, thus minimizing the number of detected variants of uncertain significance Tables 2 and 3.

At present, unfortunately, while whole genome sequencing provides the most even coverage dexual the gene sequences ie, with least likelihood of excluding gene sequences of interest and is being used in a number of research laboratories worldwide, this approach is currently generally too costly for routine diagnostic purposes.

In research laboratories, Sexual by whole exome or whole genome sequencing can provide not only the means by which to detect mutations within a large set of known DSD-related genes simultaneously, but sexual to identify new causative genes.

In clinical diagnostic laboratories, however, the pre-selected gene set or gene panel approach is currently most widely utilized in the UK for the simultaneous mutation analysis of multiple genes. Despite the power of NGS, there are nevertheless several obstacles that usually require to be overcome in a diagnostic laboratory, prior to the introduction of NGS methodology. A data analysis pipeline must be generated that is able to reliably map the millions of sequence reads to the genome, identify sequence variants, and then filter and extract a small number of likely pathogenic mutations from a very large dataset of detected sequence variants.

A particular challenge is the determination of pathogenicity of missense mutations amino acid substitutionsdespite a range of available computer algorithms for this purpose. Increasing economic constraints sexual health spending generates a necessity to justify the clinical utility of investigation of affected individuals. Newer technologies are becoming more affordable but, even where available, at present their expense may restrict their wider application.

In developed countries, obtaining a molecular diagnosis for a DSD is still only possible in less than half of affected individuals. Genomic or exomic sequencing therefore, offers the opportunity to identify additional genes ppt mechanisms associated with the development of these conditions, sexual improve diagnostic rates and, ultimately, to have a positive impact on management.

Optimal care for infants and adolescents with DSD requires an experienced multidisciplinary team. For infants with suspected DSD, this team has a role in providing patients and parents disorder information regarding diagnosis, sex assignment, and treatment options. In addition, the clinical team should have links to a wider differentiation team that consists of specialists from adult endocrinology, plastic surgery, gynecology, clinical genetics, clinical biochemistry, adult clinical psychology and social work and, if possible, ppt links to a clinical ethics forum.

Shortly ppt birth major decisions are made, including sex assignment and genital surgery, without knowledge of orientation, interests, or needs of the future adolescent and adult. The Chicago Consensus of stated that difrerentiation assignment cannot solely be based on genital appearance but should include consideration of the diagnosis, surgical options, dlsorder for lifelong replacement therapy, the potential for fertility, views of the family, and circumstances relating to cultural practices.

Ppt addition, it has implications for the long-term management of domains such as hypogonadism, subfertility, gonadal tumorigenesis, sexual function, gender identity, and quality of life. It is also possible that there may be more cases of complex hypospadias and micropenis that may require expert input for reconstructive surgery later in life.

It is likely that practice has also been ppt by those cases of XY DSD who were raised as girls and who disorder gender dysphoria. However, even in circumstances in which the person has been prenatally exposed to high levels of testosterone and reared as girl from birth, a female adult gender identity is the rule rather than the exception.

Early management in DSD has been based on the need to establish sex of rearing. Thereafter, medical and surgical differentiation has been used to reinforce this decision. Feminizing surgery comprises clitoroplasty, labioplasty, and vaginoplasty.

It is performed to allow menstrual flow, permit vaginal intercourse, and achieve a pleasing cosmetic result. There is no evidence to determine the best timing for clitoral reduction or vaginoplasty and there are no long-term studies comparing the functional, cosmetic, and psychological differentiation of early versus delayed after puberty reconstructive surgery.

Some parents may consider early genital surgery as a mechanism that could protect their child from the risk of future stigma, however a thorough discussion of the controversies around undertaking or withholding early genital surgery is imperative in informing decisions. On the other hand, altered physical sex development does not usually represent a surgical ppt for newborns. Psychological support to parents being given the diagnosis of DSD to their newly born child may be more important than discussing surgical procedures with them.

These conditions present significant parenting stress and reduced adaptive coping capacity, irrespective of the degree of genital ambiguity. In the case of CAH, steroid replacement may induce reduction of the clitoris after a few months of treatment. Vaginal dilation is first line therapy for the girls with ppt hypoplasia to permit menstruation 70 but can be deferred where there is no uterus, until such time that the girl is sexually active.

Moreover, most surgical interventions are irreversible and may restrict later options for sex reversal. In conditions associated with significant risk of gender dysphoria early surgery may also compromise future options.

In boys with partial gonadal dysgenesis, Leydig cell function may be sufficient for spontaneous pubertal development 77 — 79 and, therefore, the current ssexual is to leave disorder gonads in place. In view of the increased risk of GCC in diffetentiation testes, laparoscopy and early orchidopexy is performed at 6—12 months of age allowing for regular palpation, ultrasound, and biopsy. In girls with partial gonadal dysgenesis, the possibility of androgen production during puberty, the expected infertility and the high risk of GCC, usually lead to differenntiation decision sexual gonadectomy during early or late childhood.

Although past sexual was difcerentiation prophylactic removal of the gonads in females with complete androgen insensitivity syndrome CAIS as soon as the diagnosis is confirmed, disorder is more common now, as in PAIS, to leave the gonads in place until puberty is complete, because it allows spontaneous pubertal sexual without estrogen replacement and allows the adolescent to be involved in the discussions around surgery.

Given the practice of prophylactic gonadectomy in most cases in the past, data on GCC risk in adults are still lacking, but have been estimated to range from 0.

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Disorders of sex development. 1. Disorders of sex development (DSD); 2. It is a complex topic but actually if you understand it, it will be very. Normal Sexual differentiation Clinical approach to case of infants 2. disorder of sexual differentiation (10%) true hermaphodite %.

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disorder of sexual differentiation ppt

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disorder of sexual differentiation ppt

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