Disorders of Sex Development



Disorders of Sex Development


Sareea Al Remeithi and Diane Katherine Wherrett


Genetic sex is determined at the time of fertilization, but carrying out the encoded genetic directives that lead to sexual differentiation takes place over 14 weeks of embryonic and fetal development. An error or fault in this process may result in a disorder of sex development (DSD), defined as a discrepancy in the genetic, gonadal, or genital makeup of an individual. This part reviews (1) normal fetal sexual differentiation; (2) an approach to the recognition and diagnosis of neonates who may have a DSD; and (3) the classification, clinical features, and general management principles of DSDs, with the focus on perinatal issues.



Fetal Sexual Determination and Differentiation


Genetic Control of Fetal Gonadal Determination and Differentiation


The embryo and early fetus, regardless of genetic sex (i.e., 46,XX or 46,XY), are bipotential (i.e., sex indifferent) with respect to their possible sexual differentiation, having the anatomic and biochemical apparatus necessary for both male and female development. For normal male differentiation to occur, a succession of genetic and hormonal signals must be intact and occur normally.47 The classic teaching is that there is an innate tendency of the embryo and early fetus to differentiate along female lines; that is, female differentiation occurs if the signals for male differentiation are absent. However, evidence is growing that describes an active process involved in female differentiation.88 The biopotential gonad begins to differentiate at 7 weeks of gestation under the direction of both sex and autosomal chromosome gene products, which primarily act as transcription factors.



Sex Chromosomes and Role of the SRY Gene


The presence of the SRY gene on the Y chromosome causes the bipotential gonad to differentiate as a testis, and male phenotypic development follows. The presence of one, two, or more X chromosomes does not alter this process; however, the presence of more than one X chromosome (e.g., 47,XXY syndrome) results in eventual meiotic failure, loss of germ cells, and infertility. Candidate genes for an X-linked female determining factor are being investigated.3


On the other hand, early ovarian differentiation does not require two X chromosomes and thus proceeds in 45,X fetuses. Later on, in ovarian differentiation, two X chromosomes are necessary for normal formation of primordial follicles. If part or all of the second X chromosome is missing, ovarian development fails, beginning from about 15 weeks on, because the abnormal primordial follicles and oocytes degenerate rapidly through the remainder of gestation. The resulting gonad appears as an elongated, whitish streak that microscopically shows whorls of fibrous tissue lacking in germ cells or epithelial elements. This “streak” gonad is characteristic of the gonadal dysgenesis syndromes.


Y chromosome fetuses that fail to undergo testicular differentiation are believed to experience the same gonadal changes to form streak gonads, but unlike gonadal dysgenesis in patients with X chromosome abnormalities, these structures carry a high risk for the development of gonadal tumors.23 These tumors may result from the persistence of residual XY germ cells that did not degenerate or from tumorigenic loci on the Y chromosome.



Autosomal and X-Linked Genes


Although the presence or absence of the SRY gene determines the differentiation of the bipotential gonad, additional genes that are both autosomal and X-linked and located upstream and downstream from the SRY gene are involved in gonadal development and differentiation (Figure 98-1).64 Several of these genes have in common the encoding of a type of protein that functions as a transcription factor or transcription regulatory protein, which activates or represses the expression of other target genes, often in multiple tissues, thereby influencing or controlling a diverse program of cellular differentiation and proliferation during embryonic and fetal development. When gene mutation occurs, an alteration in the functional domain of the transcription factor can lead to abnormal or changed regulation (e.g., from a repressor to an activator) of downstream genes, resulting in abnormal cell differentiation or growth or neoplastic transformation. It is the occurrence of such mutations and the resulting pathologic conditions that have led to the identification and functional understanding of many of these genes. Examples of gene mutations that affect sex determination in 46,XY and 46,XX patients with DSDs are listed in Table 98-1.64



TABLE 98-1


Examples of Gene Mutations That Affect the Sex Determination, Clinical Phenotype, and Associated Anomalies



















































































































































































































Gene (Locus) Gonadal Development and External Genital Phenotype(s) Müllerian Structures Associated Disorders
Gene Mutations Described in 46,XY DSD
WT1 (WT33)
(11p13)
Dysgenetic testis
Undervirilized image; EG or normal image; EG
± Wilms tumor, renal abnormalities, gonadal tumors (WAGR, Denys-Drash, and Fraser syndromes)
MAP3K1
(5q11.2)
Dysgenetic testis    
Normal/undervirilized image; EG or normal image; EG ± None
ARX
(Xp22.13)
Dysgenetic testis
Undervirilized image; EG
Lissencephaly, epilepsy, temperature instability
ATRX
(Xq13.3)
Dysgenetic testis
Normal/undervirilized image; EG or normal image; EG
α-Thalassemia, developmental delay, dysmorphic facial features
WWOX
(16q23.3-q24.1)
Dysgenetic testis
Normal image; EG
AMH or Type II receptors
(19p13.3-13.2)
(12q12-13)
Normal gonadal development
Normal image; EG
+
NROB1 (DAX1)
(Xp21.3)
Dysgenetic testis
Normal/undervirilized image; EG or normal image; EG
± Congenital adrenal hypoplasia, hypogonadotrophic hypogonadism
DHH
(12q13.1)
Dysgenetic testis
Normal image; EG
+ Minifascicular neuropathy
DMRT1
(9p24.3)
Dysgenetic testis
Normal/undervirilized image; EG
± Facial abnormality, developmental delay, microcephaly
CBX2
(17q25)
Normal ovaries
Normal image; EG
+ None
GATA4
(8p23.1– p22)
Dysgenetic testis
Normal/undervirilized image; EG
Congenital heart disease
AR
(Xq12)
Normal/undervirilized image; EG or
normal image; EG
Spinal and bulbar muscular atrophy (SBMA) and prostate cancer
Gene Mutations Described in 46,XX DSD
SOX3 duplication
(Xq27.1)
Atrophic change in testis with loss of normal spermatogenesis
Normal/virilized image; EG
Data unavailable Microcephaly, developmental delay, growth restriction
RSPO1
(1p34.3)
Testis or ovotestis
Virilized image; EG or undervirilized image; EG
Palmoplantar hyperkeratosis, squamous cell carcinoma of the skin
Gene Mutations Described in 46,XY or 46,XX DSDs
SOX9 duplication
(17q24q25)
46,XY DSD:    
Dysgenetic testis or ovotestis ± Camptomelic dysplasia
Undervirilized image; EG or normal image; EG    
46,XX DSD:  
Gonadal histologic phenotype: not determined   None
Virilized image; EG or undervirilized image; EG    
SRY translocation
(Yp11.3)
46,XY DSD:    
Dysgenetic testis or ovotestis ± None
Undervirilized image; EG or normal image;    
EG  
46,XX DSD:   None
Testis or ovotestis    
MAMLD1
(Xq28)
46,XY DSD:    
Isolated hypospadias None
46,XX DSD:    
Streak or dysgenetic gonads + None
Abnormal image; EG    
NR5A1
(SF-1)
(9p33)
46,XY DSD:    
Dysgenetic testis ± ± Adrenal insufficiency
Normal/undervirilized image; EG or    
normal image; EG    
46,XX DSD:    
Dysgenetic gonads + None
Normal image; EG    
WNT4
(1p35)
46,XY DSD: Cleft lip, cleft palate, IUGR, tetralogy of Fallot, developmental delay, microcephaly
Dysgenetic testis  
Undervirilized image; EG  
46,XX DSD:
Ovary or ovotestis  
Normal/virilized image; EG or normal image; EG   Mayer-Rokitansky-Küster-Hauser, SERKAL syndromes


image


image


EG, External genital; IUGR, intrauterine growth restriction; SERKAL, Sex reversion, kidneys, adrenal and lung dysgenesis; WAGR, Wilms tumor, aniridia, genitourinary anomalies, and mental retardation.


Modified from Ono M, Harley VR. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol. 2013;9:79-91.




Embryology and Endocrinology


The bipotential gonads and the anlagen for the genital ducts and external genitalia are derived from the mesodermal germ layer; the exception is the urogenital sinus epithelium, which is of endodermal origin. The bipotential gonadal and genital tissues undergo morphogenesis during the embryonic period, which extends from the end of the third week, or about age 20 days, through the seventh to eighth week of gestational age. Sexual differentiation occurs in the fetal period beginning in the seventh week, when the bipotential gonad begins to differentiate as either a testis or an ovary, and proceeding until 12 to 14 weeks of fetal age, when differentiation of the internal genital ducts and external genitalia along male or female lines is largely complete.



Development of the Gonads


The gonadal blastema begins to form at 4 to image weeks in the genital ridge, located bilaterally on the medial aspect of each mesonephros. The somatic component of the gonad is made up of cells from the coelomic epithelium and the underlying mesenchyme or adjacent mesonephros.75 The germinal component comprises the primordial germ cells, which are mitotically active and migrate from the yolk sac endoderm at 24 days to reach the genital ridge at image to 6 weeks, thereby forming the indifferent gonad (Figure 98-2).53



Sex differentiation of the gonad begins at 7 weeks and denotes the onset of fetal sexual differentiation. The gonad differentiates as a testis if the SRY gene and its pathway are present and as an ovary if it is absent. The sex differences that appear in the developing gonad at this time include differentiation of cord somatic cells, changes in germ cell mitotic and meiotic activity, hormone production by the cord and interstitial (mesenchymal) cells, and development of the outer cortex. These differences are detailed in Table 98-2, and an overview is schematically represented in Figure 98-2.




Testicular Differentiation


Testicular differentiation begins at 7 to 8 weeks, when the sex cords form loops in the cortex and differentiate as the seminiferous cords; in the hilum, they anastomose to form the rete cords. From 8 weeks on, the seminiferous cords become coiled and thickened and contain 8 to 10 layers of Sertoli cells, whereas the spermatogonia remain located near the basement membrane of the cords. Leydig cells appear in the interstitium between the seminiferous cords at image to 8 weeks. They increase strikingly in number during the third month, occupy half the volume of the testis at 13 to 14 weeks, and then show a significant fall in number. Some Leydig cells are present postnatally, but histologically disappear after 3 to 6 months because of the physiologic lowering of gonadotropin stimulation. As the fetus elongates, the testis descends and occupies a more caudal position. In the sixth and seventh months, the cremaster muscle differentiates in the caudal testicular ligament to form the testicular gubernaculum, which penetrates the inguinal canal and is anchored to the connective tissue of the scrotum. The testis descends behind the peritoneum and reaches the scrotum by the eighth or ninth month; the inguinal canal closes after testicular descent is complete.33



Ovarian Differentiation


Ovarian differentiation begins at 7 weeks, as outlined previously and in Table 98-2. The sex cords in the ovary show germ cells (oogonia) undergoing repeated mitotic divisions from 7 weeks through about the fifth month. Most oogonia differentiate into oocytes between about 10 and 24 weeks; in so doing, they enter meiosis, proceeding through the first meiotic prophase. After reaching the meiotic prophase, many oocytes become surrounded by a single layer of granulosa cells to form the primordial follicles from about 15 weeks through term. Two X chromosomes are needed for differentiation of the primordial follicle. Oocytes degenerate if they are not enclosed in a follicle. During ovarian differentiation, the number of germ cells greatly increases to several million oogonia and oocytes by the fifth month. Most germ cells degenerate thereafter either before or during the primordial follicle stage, leaving about 150,000 oocytes in each ovary at birth.89



Development of the Genital Ducts


The internal genital ducts, unlike the gonads, develop from separate anlagen, from the mesonephric or wolffian ducts in the male and from the paramesonephric or müllerian ducts in the female. The wolffian ducts are formed in 26- to 32-day-old embryos; the müllerian ducts begin development at about 37 days in close association with the wolffian ducts, which serve as a guide to the caudal progression of the müllerian ducts. In the absence of the wolffian ducts, the müllerian ducts do not develop.


In the male fetus, the müllerian ducts begin to regress at 7 to image weeks, shortly after the Sertoli cells have differentiated and begun to produce anti-müllerian hormone (AMH), otherwise known as müllerian-inhibiting substance (MIS), and before the onset of local testosterone production by Leydig cells. Regression is complete by 9 weeks. Differentiation of the wolffian ducts is testosterone dependent and begins at about image weeks. The wolffian ducts differentiate into the epididymis and vas deferens, and beginning at image weeks, the seminal vesicles and their ejaculatory ducts develop at the caudal end from lateral outpouchings (Figure 98-3).



In the female fetus, müllerian duct differentiation occurs in the absence of AMH and does not require the presence of any ovarian hormone. The müllerian ducts form the fallopian tubes, uterus, and upper portion of the vagina beginning in the third month, stimulated in part by epidermal growth factor. The wolffian ducts degenerate in the absence of local testosterone and disappear by 13 weeks (see Figure 98-3). The fallopian tubes later descend with the ovaries and are included in a fold of peritoneum called the broad ligament. At birth, the position of the uterus is vertical, and uterine development is disproportionate in that the uterine cervix is twice as large as the fundus; it remains so until puberty. Maternal estrogens stimulate uterine growth in utero, so its size at birth is larger than it is at several months of age; endometrial hyperplasia may occasionally result in transient neonatal uterine bleeding. The development of the vagina depends on the caudal müllerian ducts’ contacting the endodermal epithelium of the urogenital sinus. At this junction, a multilayered, solid epithelial cord known as the vaginal plate is formed; it disintegrates beyond 4 months to form the vaginal lumen. It is not clear whether the lower portion of the vagina is derived from the urogenital sinus, with the upper portion of müllerian origin, or the vagina originates entirely from the urogenital sinus.



Development of the External Genitalia


The external genitalia in both sexes, like the gonads, are derived from common anlagen (Figure 98-4). Their inherent development is along female lines unless systemic androgens, specifically dihydrotestosterone (DHT), induce male differentiation. The genital tubercle forms early in the fourth week at the cranial end of the cloacal membrane, and on each side, the labioscrotal swellings and urogenital folds develop. Fusion of the urorectal septum with the cloacal membrane in the seventh week creates a dorsal anal membrane and a ventral urogenital membrane, which rupture in the eighth week to form the anus and urogenital orifice. Abnormal development of the urorectal septum results in anorectal malformations.



In the male fetus, the indifferent stage of the external genitalia lasts until the ninth week when, in the presence of systemic androgens, masculinization begins with lengthening of the anogenital distance (see Figure 98-4). The urogenital and labioscrotal folds fuse in the midline, beginning caudally and progressing anteriorly. The urethra develops with fusion of the urogenital folds, which form both the membranous urethra in the perineum and the penile urethra along the ventral surface of the phallus. Midline fusion of the labioscrotal folds forms the scrotal raphe, whereas the penile raphe represents the fused portions of the urogenital folds. These processes are complete in the 14-week fetus.


In the 9-week female fetus, the anogenital distance does not increase, and the urogenital folds and labioscrotal swellings do not fuse (see Figure 98-4). The labioscrotal swellings develop predominantly in their caudal portions but less so than in male fetuses and they remain unfused as they are transformed into the labia majora. The urogenital folds develop into the labia minora. The epithelium of the vaginal vestibule between the labia minora and the hymen is endodermal, being derived from the urogenital sinus, whereas the epithelium between the labia minora and majora is ectodermal in origin.54



Hormonal Control of Fetal Sex Differentiation


The fetal testes play a major role in male sex differentiation by producing two hormones, AMH and testosterone, which are major determinants of internal and external genital differentiation. On the other hand, the fetal ovaries play a negligible or no role in female sex differentiation, although they may have some steroidogenic capacity.



Fetal Gonadal Endocrine Function


Antimüllerian hormone is a large glycoprotein (molecular weight, 140,000 d) produced by the fetal Sertoli cells beginning at image weeks that induces irreversible involution of the müllerian ducts. Regression of the müllerian ducts can be induced by AMH only during a fetal age of 44 to 70 days. The gene coding for AMH is located on chromosome 19p13.3, and for the AMH receptor on chromosome 12.


The other major hormone produced by the fetal testis is testosterone (Figure 98-5). It is synthesized by the Leydig cells beginning at 8 weeks, and testicular production achieves peak serum testosterone levels at 10 to 15 weeks. In the second half of gestation, males show a gradual decline and females a rise in serum testosterone levels, so by the third trimester, males have similar or only slightly higher levels than females.79



The control of the fetal testicular synthesis of testosterone between 8 and 14 weeks is under human chorionic gonadotropin (hCG) of placental or fetal origin, which binds to fetal testes beginning at 8 weeks. In the second and third trimesters, fetal serum luteinizing hormone (LH) levels correlate with the maintenance and subsequent decline of serum testosterone.6 Follicle-stimulating hormone (FSH) receptors are present in fetal testes from 8 weeks on and may play a role in Sertoli cell or seminiferous tubule development.


The fetal ovary in the first trimester is hormonally quiescent, lacking hCG and FSH binding and the enzymes necessary for steroid synthesis. Starting at 8 weeks, the fetal ovary has aromatase activity and is capable of converting androstenedione or testosterone to estrone or estradiol, but actual production has not been demonstrated. Most estrogen that is present in the fetus is produced by placental aromatase. Amniotic fluid levels of estradiol at 12 to 16 weeks are slightly higher in females, raising the possibility of ovarian synthesis of estrogen. If it is synthesized, estradiol could play a local role in ovarian differentiation.3



Control of Genital Differentiation: Roles of Antimüllerian Hormone and Testosterone


In the absence of testes, female sex differentiation occurs regardless of whether an ovary or no gonad is present; a male fetus castrated early also undergoes female sex differentiation. This activity is in keeping with the inherent tendency of the fetus to develop along female lines.


Male sex differentiation requires bilateral testes that produce AMH from the Sertoli cell and testosterone from the Leydig cells. Antimüllerian hormone acts locally to cause regression of only the ipsilateral müllerian duct. If only one testis is present, müllerian duct development occurs on the contralateral side. Testosterone does not cause müllerian duct regression. A 46,XX female with müllerian duct regression resulting from a WNT4 mutation suggests that müllerian duct regression can be controlled by proteins other than AMH.32


Testosterone produced by the fetal testes is secreted both locally, where it stimulates differentiation of the ipsilateral wolffian duct, and systemically, where it serves as a prohormone in the masculinization of the external genitalia. If only one testis is present, the contralateral wolffian duct fails to differentiate, indicating that the systemically circulating testosterone levels are inadequate for the stimulation of wolffian differentiation. Therefore, testosterone derived from maternal sources or the fetal adrenals, as in congenital adrenal hyperplasia (CAH), does not induce wolffian development.


Although the wolffian ducts are stabilized through the effects of testosterone, the external genitalia and urogenital sinus are stimulated to undergo male differentiation by DHT, which is formed in peripheral tissues (external genitalia, liver, kidney, and bone marrow) through the conversion of testosterone by 5α-reductase. Testosterone is a weaker androgen than DHT and does not stimulate male external genital differentiation, serving instead as a prohormone for DHT in this tissue. Systemic testosterone derived from the fetal adrenals, as in CAH, or from maternal sources can induce variable masculinization of the external genitalia when it is metabolized to DHT.


Congenital absence of one testis (anorchia) is usually associated with incomplete masculinization of the external genitalia, suggesting that two testes are generally required to provide adequate systemic levels of testosterone and thus adequate DHT. The period in which DHT can induce male differentiation extends up to 12 to 14 weeks. A deficiency in androgen receptor binding results in androgen insensitivity, which may be partial or complete. In terms of fetal sex differentiation, the androgen-mediated events of wolffian duct differentiation, masculinization of the external genitalia, and growth of genital structures are either impaired or completely fail to occur, depending on the extent of the receptor-binding deficiency.



A Clinical Approach to the Infant with Suspected Disorder of Sex Development


The evaluation of the neonate with a suspected DSD requires prompt attention and a multidisciplinary team approach. Depending on the institution, the team may include neonatology, pediatric endocrinology, genetics, pediatric urology, pediatric gynecology, pediatric surgery, psychology, psychiatry, nursing, and social work. Appropriate initial assessment and management of the newborn with a DSD is essential to helping the family cope with this difficult situation. This evaluation needs to begin as soon as possible and should be approached systematically.



Clinical Indications for Disorder of Sex Development Evaluation


Most individuals with a DSD have some abnormality of their external genitalia that makes them identifiable at birth. An evaluation of a DSD is needed for patients who have male-appearing external genitalia with defects including isolated micropenis, severe hypospadias (perineal), bilateral cryptorchidism, or the presence of two defects such as hypospadias and unilateral cryptorchidism. In an infant with female-appearing external genitalia, the presence of posterior labial fusion, clitoromegaly, and labial or inguinal mass that might represent a gonad warrant evaluation for possible DSD, as does the finding of discordance of the prenatal karyotype with postnatal external genital phenotype.41 Examples of conditions that can cause genital abnormalities are listed in Table 98-3.





Physical Examination


Considerable information can be obtained by performing a careful physical examination. The findings of a normal newborn external genital examination are listed in Box 98-1. The clinical findings do not need to be overtly ambiguous to qualify for a diagnostic evaluation for DSDs. Inferences can be made regarding gonadal development and status and the degree of androgen effects. When evaluating a newborn for possible DSD, the clinical features of the external genitalia that require examination include evidence for any asymmetry, presence of palpable gonads in the labioscrotal folds, pigmentation and extent of labioscrotal folds fusion and rugosity, phallus length, breadth, and amount of erectile tissue, number of orifices in the perineum and their topography and the position and patency of the anus (Table 98-4). A useful tool to describe and grade the extent of female external genitalia virilization can be done using Prader scale (Stage I-V) (Figure 98-6), whereas calculating the external masculinization score (EMS: scale 0-12) provides an objective aggregate score to describe the extent of masculinization of external genitalia in boys (Figure 98-7).22








Gonadal Descent and Size


Gonads should be carefully palpated in the scrotum or labial area and along the inguinal canal. Only a gonad-containing testicular tissue (testis or ovotestis) can descend to a position where it is palpable (an ovary almost never descends). A small gonad (longest diameter <8 mm) may be dysgenetic, rudimentary, or result from lack of gonadotropin stimulation. The ability to detect gonads in the inguinal area can be enhanced by applying soap or oil to the skin and the examiner’s fingers to decrease friction. With the infant supine, glide two or three fingers with gentle to firm pressure along the inguinal canal toward the scrotum, repeating this action numerous times if necessary. The gonad will be felt “popping” under the fingers. With this technique, less accessible or small gonads can be palpated that would otherwise be missed. Additionally, sit the infant in a frog-leg position and, particularly with crying or increased intra-abdominal pressure, the testis may descend into the lower inguinal or scrotal region.



Penis Size


It is important to assess both the length and the amount of erectile tissue of the penis. A penis that appears small must be measured fully stretched, pressing the ruler down against the pubic ramus, depressing the suprapubic fat pad completely, and measuring to the tip of the glans only, ignoring any excess foreskin (Figure 98-8). An excellent ruler can be made by placing marks 0.5 cm apart on a wooden stick such as a tongue blade or a flexible strip. The width is measured at the midshaft of the stretched penis. A micropenis is arbitrarily defined as a penis with a normally formed urethra that opens at the tip of the glans in which the stretched length is less than 2.5 cm in the full-term neonate. The length criteria must be adjusted to take into account the smaller phallus in the premature neonate (Figure 98-9).25 The definition of a micropenis can also be used to describe a rare condition in which the penile corpora cavernosa are absent or severely deficient in size, resulting in an abnormally thin penis (Table 98-5).41







Urethral Opening


The male fetal urethral development is a hormone-dependent process that occurs at 8 to 14 weeks of gestation. During this stage, testosterone secretion is stimulated solely by the placental hCG. The main hormone involved in urethral development is DHT, which is produced from testosterone in a process catalyzed by 5α-reductase. If the foreskin is fully formed, the urethra is almost always at the tip of the glans; on rare occasions, the foreskin covers hypospadias on the glans. Hypospadias can vary from mild (off the center of the glans) to severe (at the base of the penis or on the perineum) (Figure 98-10). The prepuce in the hypospadiac penis is usually deficient ventrally and thus appears hooded. Chordee (ventral curvature of the penis) is caused by fibrotic contracture in the area of failed urethral development. The presence of severe hypospadias in a male infant indicates deficient testosterone or DHT action in the first trimester. In girls, the urethral meatus is normally a 1-mm pinhole-like or flat opening located just ventral to the vagina. Androgen exposure at 8 to 14 weeks of fetal age moves the urethral meatus ventrally on the perineum or the shaft of the phallic structure.




Vaginal Opening


The vaginal orifice, a 3- to 4-mm slit or stellate opening surrounded by heaped-up mucosa, is normally visible when the examiner lifts up the labia majora. The presence and direct visualization of the vaginal opening indicate the absence of androgen effects and the presence of a distal vagina (of urogenital sinus origin); whether a uterus (of müllerian duct origin) is also present cannot be inferred from this finding. Conversely, at 8 to 14 weeks of fetal age, exposure of the female fetus to androgens or incomplete androgen stimulation of the male fetus results in variable masculinization. This process can be mild to moderate, with posterior midline fusion of the labia majora that partially or completely covers the vaginal opening, thereby preventing its direct visualization. With severe masculinization, there is formation of a common urogenital sinus (resulting from the internal junction of the vagina and urethra) that is seen as a single 1- to 2-mm flat orifice on the perineum or shaft of the phallus.





Discussion with Family and Professional Staff


It is important to recognize that the birth of an infant with a DSD is a major stress for the family. A physician experienced in the evaluation of DSD should meet with the family as soon as possible to discuss the situation, ensuring confidentiality and privacy. Both parents should be present if possible. As part of the discussion, the infant’s genitalia should be examined with the parents. Parents are frequently afraid to look at their child’s genitalia. Showing the anatomic abnormalities to the family in a calm and professional manner helps the family bond with their child. Outline what will happen (procedures, consultations) and the time frame in which the results will be available. Review with the parents what they plan to tell relatives and friends, which is often a source of great anxiety. Many families and cultures have strong feelings about gender assignment, and these feelings must be known by the health professionals. Reassure the family that when the data from the tests are available, there will be much more information that will help determine the appropriate gender assignment. In most cases, the correct gender assignment will be apparent when the test results become available; in some cases, the gender assignment is not clear, and the options will need to be discussed with the parents.


Following are examples of scripts for answering questions commonly asked by families with children with a new diagnosis of a DSD. These are taken largely from the Clinical Guideline for the Management of DSD in Childhood, published by the Consortium on the Management of Disorders of Sex Development.34




Q: Is my child a boy or a girl?


A: Your question is very important. We wish we could tell you right this minute, but we really can’t tell yet. We will have more information after we conduct some tests. It’s hard for parents to wait for these test results, so we will try to update you every day, and you can call (give contact person’s name). Although your baby has a condition you probably haven’t heard much about, it isn’t that uncommon. We’ve encountered this before, and we’ll help you through this time of confusion. As soon as the tests are completed, we will be able to talk with you about the gender in which it makes most sense to raise your child, and we’ll give you a lot more information, too, because quite a lot is known about these variations, and we are learning more each day. We want to reassure you that our focus is on supporting you and your child in this time of uncertainty.


Q: What do we tell our friends and family while we wait for the gender assignment?


The following script may be most appropriate for talking to close family and friends. When discussing the situation with others, you may feel more comfortable just letting them know that the baby is in the hospital for tests.




A: This is important. We strongly recommend being open and honest with your friends and family about your child’s situation. Even if you don’t intend to, lying or withholding information will create a sense of shame and secrecy. Although it can be awkward to talk with family and friends about a child’s sex development, being honest signals that you are not ashamed—because you have nothing to be ashamed of—and it also allows others to provide you with the love and support you may need. Isolating yourself at this time will probably make you feel unnecessarily stressed and lonely. Talking about it will help you feel connected with others. So here is what you can tell people: Our baby was born with a kind of variation that happens more often than you hear about. Our doctors are doing a series of tests to figure out whether our baby is probably going to feel more like a boy or a girl. We expect to have more information from them within (specify realistic time frame), and then we’ll send out a birth announcement with the gender and the name we’ve chosen. Of course, as is true with any child, the various tests the doctors are doing are not going to tell us for sure who our baby will turn out to be. We’re going to go on that journey together. We appreciate your love and support and we’re looking forward to introducing you to our little one in person soon.


It also helps to let your friends and family know whether your baby is healthy or whether there are some health concerns. Finally, take some pictures of your baby’s face, and share those pictures with others!


Because of the stress produced by having a child with DSD, support from a behavioral scientist (social worker, psychologist, or psychiatrist) may be helpful for the family. It may be helpful for families to be informed about relevant credible resources listed at the end of this section.41


In addition to discussions with the family, it is important to keep the hospital staff who have contact with the family fully informed about the information that has been given to the parents. This professional candor reduces the possibility of insensitive comments made by hospital personnel to family members and is especially important in cases in which gender assignment must be delayed.



Initial Diagnostic Evaluation


In cases in which gender assignment is pending, all relevant tests should be obtained as soon as possible. A summary of the initial workup for DSD evaluation in newborns is shown in Box 98-2.





Biochemistry


Interpretation of biochemistry tests is dependent on the timing of the sample and understanding of the normal levels of hormones at that time. A blood sample should be obtained after 24 to 48 hours of life, after the time of the neonatal surge of androgens, for measurement of testosterone and 17-hydroxyprogesterone (17-OHP). It is desirable to draw extra blood so that the laboratory can save the serum for analysis of other hormones that may be indicated as the evaluation continues. Increased serum levels of testosterone occur physiologically in neonates with functioning testes at 12 to 36 hours and at 2 weeks to 4 to 6 months of age.88 The level may also increase pathologically at any time from the adrenal secretion of androgens in cases of CAH. Decreased levels of testosterone occur if Leydig cells are deficient or absent, LH activity is impaired, or there is a testosterone biosynthetic defect. Blood samples are also diagnostically useful at 1 or 2 months of age to assess the peak of hypothalamic-pituitary-testicular axis function in infancy.


An increased level of 17-OHP suggests 21- or 11β-hydroxylase deficiency and implies that any increased levels of testosterone were of adrenal rather than testicular origin in a 46,XX patient. The 17-OHP levels in premature infants are higher than those in full-term infants.40 In CAH with 21-hydroxylase deficiency, the levels of 17-OHP are often 10 to 50 times the upper limit of the normal level, making the test virtually diagnostic.


The measurement of serum AMH has been shown to correlate with Sertoli cell function.8 Similarly, inhibin B levels have been shown to rise in males in the first week of life. Its measurement is therefore useful for identifying the presence of Sertoli cells and of functional testes in newborn boys with nonpalpable gonads.8 Other tests that may be useful, depending on the clinical presentation, are measurements of LH, FSH, estradiol, precursors of testosterone, and DHT.

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Jun 6, 2017 | Posted by in PEDIATRICS | Comments Off on Disorders of Sex Development
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