gender assignment of infants

The Intersex Society of North America closed its doors and stopped updating this website in 2008. ISNA’s work is continued by interACT: Advocates for Intersex Youth , who proudly preserves this website as a historical archive. For current information, links to intersex support groups, and to connect with intersex advocates, please head to interACT: Advocates for Intersex Youth .

# How can you assign a gender (boy or girl) without surgery?

When you assign a child a gender as boy or girl, what you’re doing is labeling them a boy or girl. That’s it. You don’t need a surgeon for that.

But how do you pick a child’s gender if she or he is intersex?

The child is assigned a gender as boy or girl after tests (hormonal, genetic, radiological) have been done and the parents have consulted with the doctors on which gender the child is more likely to feel as she or he grows up.

We know, for example, that the vast majority of children with complete androgen insensitivity syndrome grow up to feel female, and that many children with cloacal exstrophy and XY chromosomes will grow up to feel male.

Why shouldn’t children with intersex be raised in a “third gender”? We advocate assigning a boy or girl gender because intersex is not, and will never be, a discrete biological category any more than male or female is, and because assigning an “intersex” gender would unnecessarily traumatize the child.

In cases of intersex, doctors and parents need to recognize, however, that gender assignment of infants with intersex conditions as boy or girl, as with assignment of any infant, is preliminary. Any child—intersex or not—may decide later in life that she or he was given the wrong gender assignment; but children with certain intersex conditions have significantly higher rates of gender transition than the general population, with or without treatment.

That is a crucial reason why medically unnecessary surgeries should not be done without the patient’s consent; the child with an intersex condition may later want genitals (either the ones they were born with or surgically constructed anatomy) different than what the doctors would have chosen. Surgically constructed genitals are extremely difficult if not impossible to “undo,” and children altered at birth or in infancy are largely stuck with what doctors give them.

← Why Doesn't ISNA Want to Eradicate Gender? What evidence is there that you can grow up psychologically healthy with intersex genitals (without normalizing surgeries)? →

• Open access
• Published: 09 February 2022

A review of the essential concepts in diagnosis, therapy, and gender assignment in disorders of sexual development

• Vivek Parameswara Sarma   ORCID: orcid.org/0000-0001-9484-7090 1  

Annals of Pediatric Surgery volume  18 , Article number:  13 ( 2022 ) Cite this article

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The aim of this article is to review the essential concepts, current terminologies and classification, management guidelines and the rationale of gender assignment in different types of differences/disorders of sexual development.

The basics of the present understanding of normal sexual differentiation and psychosexual development were reviewed. The current guidelines, consensus statements along with recommendations in management of DSD were critically analyzed to formulate the review. The classification of DSD that is presently in vogue is presented in detail, with reference to old nomenclature. The individual DSD has been tabulated based on various differential characteristics. Two schemes for analysis of DSD types, based on clinical presentation, karyotype and endocrine profile has been proposed here. The risk of gonadal malignancy in different types of DSD is analyzed. The rationale of gender assignment, therapeutic options, and ethical dimension of treatment in DSD is reviewed in detail.

The optimal management of different types of DSD in the present era requires the following considerations: (1) establishment of a precise diagnosis, employing the advances in genetic and endocrine evaluation. (2) A multidisciplinary team is required for the diagnosis, evaluation, gender assignment and follow-up of these children, and during their transition to adulthood. (3) Deeper understanding of the issues in psychosexual development in DSD is vital for therapy. (4) The patients and their families should be an integral part of the decision-making process. (5) Recommendations for gender assignment should be based upon the specific outcome data. (6) The relative rarity of DSD should prompt constitution of DSD registers, to record and share information, on national/international basis. (7) The formation of peer support groups is equally important. The recognition that each subject with DSD is unique and requires individualized therapy remains the most paramount.

The aim of this article is to review the essential concepts, current terminologies and classification, management guidelines, and the rationale of gender assignment in different types of differences/disorders of sexual development (DSD). The basics of the present understanding of normal sexual differentiation and psychosexual development were reviewed. The current guidelines, consensus statements along with recommendations in management of DSD were critically analyzed to formulate the review. The classification of DSD that is presently in vogue is presented in detail, with reference to old nomenclature. The individual DSD has been tabulated based on various differential characteristics. Two schemes for analysis of DSD types, based on clinical presentation, karyotype, and endocrine profile has been proposed here. The risk of gonadal malignancy in different types of DSD is analyzed. The rationale of gender assignment, therapeutic options, and ethical dimension of treatment in DSD is reviewed in detail.

The normal sexual differentiation

The normal pattern of human sexual development and differentiation that involves specific genetic activity and hormonal mediators [ 1 , 2 ] is explained by the classical Jost’s paradigm; the essence of which is narrated below [ 3 ].

The establishment of chromosomal sex (XX or XY) occurs at the time of fertilization. The variations in sex chromosome include XO, XXY or mosaicism as in XO/XY.

Chromosomal sex influences the determination of the gonadal sex, thus differentiating the bipotential gonadal ridge into testis or ovary. (Variations in gonadal sex include ovotestis and streak gonad.) The SRY gene (referred to as the testis-determining gene) on the short arm of Y chromosome directs the differentiation into testes, with formation of Leydig and Sertoli cells [ 4 , 5 ].

The sex phenotype (internal and external genitalia) is determined by the specific hormones secreted by the testes, which translates the gonadal sex into phenotype. Testosterone secretion by Leydig cells promotes Wolffian duct differentiation into vas deferens, epididymis, and seminal vesicles. The Wolffian ducts regress in the absence of androgenic stimulation. Testosterone is converted to dihydrotestosterone (DHT), by 5-alpha reductase, which results in masculinization of external genitalia, closure of urethral folds, and development of the prostate and scrotum. In the absence of influence of SRY gene, the development of bipotential gonad will evolve along the female pathway. Thus, the Mullerian ducts develop (even without any obvious hormonal input) into the uterus, fallopian tubes, and the proximal 2/3 of vagina. DHT is also important for the suppression of development of the sinovaginal bulb, which gives rise to the distal 1/3 of vagina. The fact that internal duct development reflects the ipsilateral gonad (due to the paracrine effect of sex hormones) is an important consideration in the understanding of specific types of DSD. The anti-Mullerian hormone (AMH) from Sertoli cells of Testis is vital for the regression of Mullerian structures. Therefore, Wolffian structures will develop on one side, along with Mullerian duct regression, only in the presence of a fully functional testis. But, Mullerian duct structures develop on one side even in the presence of an ipsilateral streak gonad. The genital tubercle develops as a clitoris, the urethral folds form the labia minora, and the labioscrotal swellings form the labia majora [ 1 , 2 , 4 , 5 , 6 ].

The concept of psychosexual development was added to the above sequence by Money et al. [ 7 ]. The brain undergoes sexual differentiation consistent with the other characteristics of sex. It is proposed that androgens organize the brain in early development and pubertal steroids activate the same, leading to masculine behavior. The sexual differentiation of genitalia occur in first 2 months of pregnancy, while sexual differentiation of brain occurs in the second half of pregnancy, and hence these processes can be influenced independently. Therefore, the extent of virilization of genitalia may not reflect the extent of masculinization of brain [ 8 , 9 ].

Psychosexual development is a complex and multifactorial process influenced by brain structure, genetics, prenatal and postnatal hormonal factors, environmental, familial, and psychosocial exposure [ 10 , 11 , 12 ]. Psychosexual development is conceptualized as three components: (1) gender identity is defined as the self-representation of a person as male, female or even, neither. (2) Gender role (sex-typical behavior) describes behavior, attitudes and traits that a society identifies as masculine or feminine. (3) Sexual orientation denotes the individual responsiveness to sexual stimuli, which includes behavior, fantasies, and attractions (hetero/bi/homo-sexual).

Psychosexual development is influenced by various factors such as Androgen exposure, sex chromosome genes, brain structure, family dynamics and social structure. With reference to altered psychosexual development, two conditions are important to be recognized and differentiated. (1) Gender dissatisfaction denotes unhappiness with the assigned sex, the etiology of which is poorly understood. (With respect to subjects with DSD, it has to be remembered that homo-sexual orientation or cross-sex interest is not considered an indication of incorrect gender assignment.) (2) Gender dysphoria (GD) is characterized by marked incongruence between the assigned gender and experienced/expressed gender, which is associated with clinically significant functional impairment. (It can occur in the presence or absence of DSD) [ 12 , 13 , 14 ].

The term “disorders/differences of sex development” (DSD) is defined as congenital anomalies in which development of chromosomal, gonadal, or phenotypic sex (including external genitalia/internal ductal structures) is atypical. In a wider perspective, DSD includes all conditions where chromosomal, gonadal, phenotypical, or psychological sex are incongruent. The three components of psychosexual development also may not always be concordant in DSD [ 15 , 16 ].

A greater understanding of underlying genetic and endocrine abnormalities has necessitated refinement in terminologies and classification of DSD. The newer classification of DSD aims to be more precise, specific, flexible, and inclusive of advances in genetic diagnosis, while being sensitive to patient concerns (Table  1 ). Terms such as intersex, hermaphrodite, pseudohermaphrodite, and sex reversal are avoided, to this end, in diagnostic terminologies. Presently, a specific molecular diagnosis is identified only in about 20% of all DSD. The majority of virilized 46 XX infants will have CAH, but only 50% of 46 XY DSD will have a definitive diagnosis [ 16 , 17 ].

For the purpose of understanding of the basic pathology and ease of comprehension, DSD can be classified as follows:

Sex chromosomal DSD: here, the sex chromosome itself is abnormal. This includes XO (Turner syndrome), XXY (Klinefelter’s syndrome), mosaic patterns of XO/XY (Mixed Gonadal Dysgenesis and Partial Gonadal Dysgenesis), XX/XY (Ovotesticular DSD), and even SRY-positive XX in 46 XX testicular DSD (de la Chapelle syndrome). These are essentially genetic anomalies characterized by a varying degrees of gonadal dysgenesis/abnormal gonadal differentiation secondary to the sex chromosome defect and in certain situations, associated systemic abnormalities and increased risk of malignancies. The phenotypic sex (internal ductal structures and external genitalia) reflects the gonadal sex.

Disorders of gonadal development: these are characterized by abnormal gonadal development, in the absence of any obvious sex chromosomal abnormality, i.e., Karyotype is either 46 XX or 46 XY. It includes 46 XY complete gonadal dysgenesis (Swyer syndrome), 46 XY partial gonadal dysgenesis, 46 XY ovotesticular DSD, 46 XX pure gonadal dysgenesis (Finnish syndrome) and 46 XX ovotesticular DSD. Here also, the phenotypic sex reflects the gonadal sex (streak or dysgenetic gonads/ovotestis).

Abnormalities in phenotypic sex secondary to hormonal defects: these are characterized by normal chromosomal sex (46 XX or 46 XY) and gonadal sex (testes/ovaries), but abnormal phenotype (internal ductal and/or external genital) due to defects in hormonal function. In 46 XY DSD, this can be due to defects in synthesis or action of androgens or less commonly, AMH. In 46 XX DSD, this is due to androgen excess, as in Congenital Adrenal Hyperplasia, or less commonly, gestational hyperandrogenism.

Primary endocrine abnormalities: These are characterized by a severe underlying endocrine abnormality, as in congenital hypogonadotropic hypogonadism or pan-hypopitutarism.

Malformation syndromes: these are characterized by the presence of genital abnormalities due to severe congenital anomalies including persistent cloaca, cloacal exstrophy, Mullerian agenesis/MRKH syndrome, or vaginal atresia.

The common pattern of correlation of gonadal sex with internal duct structure development is summarized in Table  2 . The cardinal characteristics of chromosomal, gonadal, and phenotypic sex in the individual types of DSD is summarized in Table  3 .

The genetic testing in DSD

For a sex chromosome DSD, no further genetic analysis is required. However, a DSD with 46 XX or 46 XY karyotype, the underlying etiology may be a monogenic disorder where the candidate gene has to be analyzed. The algorithm of genetic analysis of DSD is defined according to the results of sex chromosome complement (karyotyping/array CGH or SNP array) and presence of regions of Y chromosome (FISH/QFPCR). The next step is to study specific genes involved in gonadal development by techniques including Sanger sequencing combined with MLPA to assess specific genetic defects. Further analysis includes evaluation for causes of monogenic DSD or analysis of copy number variations (CNV) or both. Panels for candidate genes (CYP21A2 in CAH, AR in androgen insensitivity syndrome) provide rapid and reliable results. The evolving use of whole exome sequencing (WES) and whole genome sequencing (WGS) aim to identify previously unrecognized genetic etiology of DSD.

The further characterization of 46 XY DSD

The further characterization of individual types of 46 XY DSD based on endocrine and genetic evaluation is summarized in Table  4 . The selective use of the following investigations is required in 46 XY DSD to arrive at a specific diagnosis of the subtype:

Assay of serum testosterone, LH and FSH.

hCG stimulation test, to assess response in testosterone levels.

Assay of AMH, to detect the presence of functioning testicular tissue.

Testosterone: dihydrotestosterone (DHT) ratio.

Testosterone: androstenedione ratio.

ACTH test, for the diagnosis of testosterone biosynthesis defects.

Specific substrates like progesterone, 17-OHP, and 1-OH pregnenelone, for typing of Androgen biosynthesis defects.

Ultrasound scan/MRI and laparoscopy for the detection of Mullerian structures.

Gonadal biopsy for the diagnosis of ovotesticular DSD and gonadal dysgenesis.

Genetic testing including screening of androgen receptor gene for mutations, Molecular testing for 5-alpha reductase-2 gene mutations, androgen receptor expression, and androgen binding study in genital skin fibroblasts.

The further characterization of 46 XX DSD is summarized in Table  5 . The classification of the major types of DSD based on the different clinical manifestations is summarized in Table  6 .

Gonadal dysgenesis syndromes

There are five common patterns of gonadal dysgenesis syndromes, in addition to the dysgenetic ovotestis which is found in 46 XX or 46 XY ovotesticular DSD.

46 XY complete gonadal dysgenesis (Swyer syndrome)

46 XY partial gonadal dysgenesis (Noonan syndrome)

45 XO/46 XY mixed gonadal dysgenesis

46 XX pure gonadal dysgenesis (Finnish syndrome)

45 XO Turner’s syndrome.

Gender assignment in DSD

The classical “optimal gender policy” involved early sex assignment and surgical correction of genitalia and hormonal therapy, with the objective of an unambiguous gender of rearing, that will influence the future gender identity and gender role [ 7 , 11 ]. The genital phenotype (characteristics of genitalia) has historically been the guide for gender assignment, considering esthetic, sexual, and fertility considerations. This perspective, which assumes psychosexual neutrality at birth, has been challenged now, with the present focus shifting to the importance of prenatal and genetic influences on psychosexual development. In addition to the progress in the diagnostic techniques and therapeutic modalities, there has been greater understanding of the associated psychosocial issues and acceptance of patient advocacy [ 19 , 20 , 21 ].

Factors to be considered for gender assignment in DSD

The most common gender identity outcome, observed incidence of GD, and requirement of gender reassignment in the specific type of DSD from available data.

The most common pattern of psychosexual development in the particular DSD, consistent with established neurological characteristics.

The requirement of genital reconstructive surgery to conform to the assigned sex.

The estimated risk of gonadal malignancy and need for gonadectomy (Table  7 ).

The requirement, possible response, and timing of HRT.

The expected post-pubertal cosmetic and functional outcome of genitalia, after reconstruction where required.

The potential for fertility, even with the presumed aid of assisted reproduction techniques.

Though GD in patients with DSD influences, the choice of gender assignment (and reassignment), sexual orientation, and gender-atypical behavior do not affect the decision-making process in gender assignment of DSD [ 22 ].

Gender assignment in neonates should be done only after expert evaluation. The evaluation, therapy, and long-term follow-up should only be done at a centre with an experienced multidisciplinary team. The multidisciplinary team for management of DSD should include pediatric subspecialists in endocrinology, surgery/urology, genetics, gynecology, and psychiatry along with pediatrician/neonatologist, psychologist, specialist nurse, social worker, and medical ethicist. The core group will vary according to the type of DSD. All individuals with DSD should receive the appropriate gender assignment [ 22 , 23 , 24 , 25 ]. The patient and family should be able to have an open communication and participation in the decision-making process. The concerns of patients and their families should be respected and addressed in strict confidence.

The rationale of gender assignment in different clinical conditions of DSD

The usually recommended gender assignment guidelines in different clinical types of DSD is summarized in Table  8 .

46 XX DSD—congenital adrenal hyperplasia (CAH)

In CAH, female gender identity is the most common outcome despite markedly masculinized gender-related behavior. Patients diagnosed in the neonatal period, particularly with lower degrees of virilization, should be assigned and reared as female gender, with early feminizing surgery. GD is rare when female gender is assigned. Those with delayed diagnosis and severely masculinized genitalia need evaluation by a multidisciplinary team. Evidence supports the current recommendation to rear such infants, even with marked virilization, as females [ 18 , 19 , 22 , 23 , 26 ]. A psychological counseling for children with CAH and their families, focused on gender identity and GD, is recommended.

46 XY complete gonadal dysgenesis

It is recommended to rear these children as female, due to following considerations: (a) these patients have typical female psychosexual development. (b) Reconstructive surgery is not required for the external genitalia to be consistent with female gender. (c) Hormonal replacement therapy (HRT) is required at puberty as streak gonads should be removed in view of high risk of gonadal malignancy. (d) Pregnancy is feasible with implantation of fertilized donor eggs and hormonal therapy [ 19 , 22 , 23 ].

Complete androgen insensitivity syndrome (CAIS)

It is recommended that subjects with CAIS should be reared as female, due to the following considerations: (a) they have well documented female-typical core psychosexual characteristics, with no significant GD, in accordance with the proposed absence of androgenization of the brain. (b) Surgical reconstruction of the genitalia is not required for consistency with female gender, though vaginoplasty may be necessary. (c) HRT is required with estrogens after gonadectomy, but testosterone replacement is untenable due to androgen resistance [ 18 , 19 , 22 , 23 , 26 ].

5-alpha reductase deficiency

Male gender assignment is usually recommended due to the following considerations: (a) the genital tissue is responsive to androgens. (b) The potential for fertility. (c) The reported high incidence of subjects requesting female-to-male gender reassignment after puberty*. (d) HRT is not required at puberty for patients reared as male, if testes are not removed. (e) As the risk of gonadal malignancy is low, testes can potentially be retained. (f) They are very likely to have a male gender identity.*(As most neonates with this disorder have female external genitalia at birth, they are reared as females. Profound virilization occurs at puberty, with a gender role change from female to male during adolescence in up to 63% cases.) About 60% of these patients, assigned female in infancy and virilizing at puberty, and all who are assigned male, live as males. When the diagnosis is made in infancy, the combination of male gender identity in the majority and the potential for fertility, should be considered for gender assignment [ 19 , 22 , 23 ].

17-beta-HSD-3 deficiency

Classical features are that of an undervirilized male. Some of the affected patients with feminine genitalia at birth are reared as females. Virilization occurs at puberty, with gender role change from female to male in up to 64% cases. They are highly likely to identify as males. Male gender assignment is recommended in partial defects. But there is no strong data to support male gender assignment, as in 5-alpha reductase deficiency. The other considerations against male gender assignment are the lack of reported cases of fertility and the intermediate risk of germ cell tumors. Hence, regular testicular surveillance is required for those reared as male, with retained testes. Therefore, gender assignment should be made considering all the above factors [ 18 , 19 , 22 , 23 , 26 ].

Partial androgen insensitivity syndrome (PAIS)

Infants with PAIS are assigned to male/female gender, depending partially on the degree of undervirilization. The virilization at puberty is also variable and incomplete. The response to hCG stimulation test/testosterone therapy can serve as a guide to the possible sex of rearing. The phenotype is highly variable in PAIS, which is correspondingly reflected in the sex of rearing. The gender identity has considerable fluidity in PAIS, though gender identity is usually in line with the gender of rearing. Though fertility is possible if the testes are retained, it should be remembered that there is an intermediate risk of gonadal germ cell tumors. Hence, gender assignment in these patients is a complex, multifactorial process [ 18 , 19 , 22 , 23 , 26 ].

47 XXY Klinefelter’s syndrome and variants

They usually report a male gender identity, but with a putative high incidence of GD, which needs to be elaborated in larger series.

Mixed gonadal dysgenesis

The genital phenotype is highly variable. The prenatal androgen exposure, internal ductal anatomy, testicular function at and after puberty, post-puberty phallic development, and gonadal location have to be considered to decide the sex of rearing.

• Ovotesticular DSD

These entities were previously referred to as “true hermaphroditism”, signifying the presence of both testicular and ovarian tissue, though dysgenetic, in the same subject. The three patterns seen are as follows:

46 XX/XY–33% of ovotesticular DSD, with testis and ovary/ovotestis.

46 XX–33% of ovotesticular DSD, with dysgenetic ovotestis.

46 XY–7% of ovotesticular DSD, with dysgenetic ovotestis.

This is characterized by ambiguity of genitalia or severe hypospadias at birth, with secondary sexual changes at puberty, corresponding to the relative predominance of ovarian/testicular tissue. The management depends on the age at diagnosis and anatomical differentiation. Either sex assignment is appropriate when the diagnosis is made early, prior to definition of gender identity. The sex of rearing should be decided considering the potential for fertility, based on gonadal differentiation and genital development. It should be ensured that the genitalia are, or can be made, consistent with the chosen sex [ 19 , 22 , 23 , 24 , 25 ].

General guidelines for surgery and HRT in DSD

Feminizing genitoplasty.

Surgery for correction of virilization (clitoral recession, with conservation of neurovascular and erectile structures, and labioplasty) should be carried out in conjunction with the repair of the common urogenital sinus (vaginoplasty). The current recommendation is to perform early, single-stage feminizing surgery for female infants with CAH. It is opined that correction in first year of life relieves parental distress related to anatomic concerns, mitigates the risks of stigmatization and gender identity confusion, and improves attachment between the child and parents. The current recommendation is the early separation of vagina and urethra, the rationale of which includes the beneficial effects of estrogen for wound healing in early infancy, limiting the postoperative stricture formation and avoidance of possible complications from the abnormal connection between the urinary tract and peritoneum through the Fallopian tubes. Surgical reconstruction in infancy may require refinement at puberty. Vaginal dilatation should not be undertaken before puberty. An absent or inadequate vagina, requiring a complex reconstruction of at high risk of stricture formation, may be appropriately delayed. But, the need for complete correction of urogenital sinus, prior to the onset of menstruation, is an important consideration [ 19 , 22 , 23 , 24 , 25 , 26 ].

Male genital reconstruction

The standard timing and techniques of operative procedures for correction of ventral curvature and urethral reconstruction, along with selective use of pre-operative testosterone supplementation is advised when male sex of rearing is adopted. The complexity of phallic reconstruction later in life, compared to infancy, is an important consideration in this regard. There is no evidence that prophylactic removal of discordant structures (utriculus/pseudovagina, Mullerian remnants) that are asymptomatic, is required. But symptoms in the future may mandate surgical removal. In patients with symptomatic utriculus, removal can be attempted laparoscopically, though it may not be practically feasible to preserve the continuity of vas deferens [ 19 , 22 , 23 , 24 , 25 ].

Gonadectomy

The gonads at the greatest risk of malignancy are both dysgenetic and intra-abdominal. The streak gonad in a patient with MGD, raised male should be removed by laparoscopy in early childhood. Bilateral gonadectomy (for bilateral streak gonads) is done in early childhood for females with gonadal dysgenesis and Y chromosome material, which should be detected by techniques like FISH and QFPCR. In patients with defects of Androgen biosynthesis raised female, gonadectomy is done before puberty. The testes in patients with CAIS and those with PAIS, raised as females, should be removed to prevent malignancy in adulthood. Immunohistochemical markers (IHM) that can serve to identify gonads at risk of developing malignancy include OCT 3/ 4, PLAP, AFP, beta-Catenin and CD 117. Early removal at the time of diagnosis (along with estrogen replacement therapy) also takes care of the associated hernia, psychological problems associated with the retained testes and risk of malignancy. Parental choice allows deferment until adolescence, in view of the fact that earliest reported malignancy in CAIS is at 14 years of age. A scrotal testis in gonadal dysgenesis is at risk of malignancy. Current recommendations are surveillance with testicular biopsy at puberty to detect premalignant lesions, which if detected, is treated with local low-dose radiotherapy (with preliminary sperm banking). Also, patients with bilateral ovotestes are potentially fertile from the functioning ovarian tissue. Separation of ovarian and testicular tissue, though challenging, is preferably done early in life [ 19 , 22 , 23 , 24 , 25 , 26 ].

Hormonal therapy/sex steroid replacement

Hormonal induction at puberty in hypogonadism should attempt to replicate normal pubertal maturation to induce secondary sexual characteristics, pubertal growth spurt, optimal bone mineral accumulation together with psychosocial support for psychosexual maturation. Treatment is initiated at low doses and progressively increased. Testosterone supplementation in males (initiated at bone age of 12 years) and estrogen supplementation in females (initiated at bone age of 11 years) is given accordingly for established hypogonadism. In males, exogenous testosterone is generally given till about 21 years, while the same in females is variable. Also, in females a progestin is added after breakthrough bleeding occurs, or within 1–2 years of continuous estrogen. No evidence of benefit exists for addition of cyclical progesterone in females without uterus [ 22 , 23 , 24 , 25 ].

The advances in molecular diagnosis of DSD

The advent of advanced tools for genetic diagnosis has enabled specific diagnosis to be made by molecular studies. WES and WGS represent evolving translational research that help to identify novel genetic causes of DSD. The techniques for identification of novel genetic factors in DSD have evolved from the use of CGH and custom array sequencing to the use of next generation sequencing (NGS) which mainly includes polymerase-based and ligase-based techniques. The importance of molecular diagnosis in DSD lies in the guidance of management in relation to possible gender development, assessment of adrenal and gonadal function, evaluation of the risk of gonadal malignancy, assessment of the risk of familial recurrence, and prediction of possible morbidities and long-term outcome. Hence, the advances in molecular diagnosis of DSD constitute a rapidly evolving frontier in the understanding and therapy of DSD.

The ethical dimension in DSD

The predominant ethical considerations in management of DSD are twofold. Firstly, when the components of biological sex (the sexual profile of genome, gonads, phenotype, endocrine and neurological status) align strongly, prediction of gender identity and recommendations for sex assignment can be made accordingly. The more discordant the determinants of biological sex, more variation in subsequent components of psychosexual development. Secondly, irreversible anatomic and physiologic effects of surgical assignment of sex have to be avoided, especially when the components of biological sex do not strongly align. The objective in such situations should be to delay such treatment till the appropriate age [ 24 , 25 , 26 ].

The arguments favoring recognition of DSD as an alternate gender, with delayed sex assignment and deferred surgical therapy has gained ground over the past decades, highlighted by certain judicial interventions across the globe. In this regard, it has to be emphasized that a transgender state, without incongruity of biological sex, has to be clearly distinguished from a DSD. Though differences in psychosexual development can occur in DSD, the vast majority of clinically diagnosed DSD (CAH, MGD, 46 XY DSD) have the anatomic and physiological consequences of altered components of biological sex. The issues in these subjects are not only confined to the genitalia, but also include problems that can include life-threatening cortisol deficiency, features of hypogonadism and urogenital sinus, and even the risk of gonadal malignancy. The early identification and correction of each issue is vital, and the best available window for the same is limited and usually, early in life. It is some of the less frequently encountered types of DSD (ovotesticular DSD, 17-BHSD deficiency, PAIS) that invariably require a more complex decision-making process. The diagnostic and therapeutic approach in the majority of clinically encountered DSD requires a structured scientific approach, with due consideration of the intricacies of psychosexual development.

The optimal management of different types of DSD in the present era requires the following considerations: (1) establishment of a precise diagnosis, employing the advances in genetic testing and endocrine evaluation. (2) A multidisciplinary team is required for the diagnosis, evaluation, gender assignment and follow-up of these children, and during their transition to adulthood. (3) Deeper understanding of the issues in psychosexual development in DSD is vital for therapy. (4) The patients and their families should be an integral part of the decision-making process. (5) Recommendations for gender assignment should be based upon the specific outcome data. (6) The relative rarity of DSD should prompt constitution of DSD registers, to record and share information, on national/international basis. (7) The formation of peer support groups is equally important. The recognition that each subject with DSD is unique and requires individualized therapy remains the most paramount.

Availability of data and materials

Available on request.

Abbreviations

Disorders of sexual differentiation

• Congenital adrenal hyperplasia

Complete androgen insensitivity syndrome

Partial androgen insensitivity syndrome

Follicular stimulating hormone

Leutinizing hormone

Human chorionic gonadotropin

Fluorescence in situ hybridization

Quantitative fluorescence polymerase chain reaction

Comparative genomic hybridization

Multiplex ligand-dependent probe amplification

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Guerrero-Fernández J, Azcona San Julián C, Barreiro Conde J, de la Vega JA B, Carcavilla Urquí A, Castaño González LA, et al. Guía de actuación en las anomalías de la diferenciación sexual (ADS)/desarrollo sexual diferente (DSD) [Management guidelines for disorders/different sex development (DSD)]. An Pediatr (Barc). 2018;89(5):315 e1-315.e19.

Houk CP, Hughes IA, Ahmed SF, Lee PA. Summary of consensus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics. 2006;118:753–7.

van der Zwan YG, Callens N, van Kuppenveld J, Kwak K, Drop SL, Kortmann B, et al. Long-term outcomes in males with disorders of sex development. J Urol. 2013;190:1038–42.

Warne G, Grover S, Hutson J, Sinclair A, Metcalfe S, Northam F, et al. A long-term outcome study of intersex conditions. J Pediatr Endocrinol Metab. 2005;18:555–67.

Fisher AD, Ristori J, Fanni E, Castellini G, Forti G, Maggi M. Gender identity, gender assignment and reassignment in individuals with disorders of sex development: a major of dilemma. J Endocrinol Investig. 2016;39(11):1207–24.

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Acknowledgements

The sincere guidance and help provided by Dr. K Sivakumar, Professor and Head, Department of Pediatric Surgery, Government Medical College, Thiruvananthapuram, Kerala, is gratefully acknowledged.

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Sarma, V.P. A review of the essential concepts in diagnosis, therapy, and gender assignment in disorders of sexual development. Ann Pediatr Surg 18 , 13 (2022). https://doi.org/10.1186/s43159-021-00149-w

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• Disorders of sexual development
• Ambiguous genitalia
• Gonadal dysgenesis
• Psychosexual development
• Gender dysphoria

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Assigned Gender

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Assigned Gender , also called Assigned Gender at Birth (AGAB) , Gender Assigned at Birth (GAAB) , Designated Gender at Birth (DGAB) or Assigned Sex at Birth (ASAB) , is a gender or sex assigned to infants, usually based on genitalia alone and reported on the infant's birth certificate. [1] [2] [3] [4]

There are various definitions and versions of AGAB and its overall concept. These include:

• AGAB (Assigned Gender at Birth): Referring to one's assigned sex. An example of this is AMAB (Assigned Male at Birth). Despite the terminological difference between sex and gender, sex assignment is commonly referred to as an assigned gender; [5]
• AGAB (Assigned Gender at Birth): A less common use of the term - referring to the intangible decision made by the parent(s)/guardian(s) to treat the infant as a certain gender identity, which usually follows on throughout childhood and teenagehood. An example of this is AMAB (Assigned Male / Man /Boy at Birth); [6]
• AGAA (Assigned Gender at Age): Referring to the intangible decision made by the parent(s)/guardian(s) to treat the infant, child, or teenager as a certain gender identity. An example of this is AMAC (Assigned Boy At Childhood); citation needed
• CAGAB (Coercively Assigned Gender at Birth) / FAGAB (Forcefully Assigned Gender at Birth): Referring to one's coercive/forced sex assignment, usually in cases where an infant's body is medically altered to reflect either male or female genitalia. An example of this is CAMAB (Coercively Assigned Male at Birth); [7] [8]
• IAGAB ( Intersex /Incorrectly Assigned Gender at Birth): Referring to an intersex infant's sex assignment, usually male or female especially in countries where intersex is not legally recognized or is unable to be assigned in one's birth certificate. May also refer to an incorrect assignment, especially in cases where the infant's intersex traits are not externally visible; [9]
• ASAB (Assigned Sex at Birth): Referring to one's assigned sex, based on the infant's birth certificate. This is usually used over AGAB as to affirm the differences between sex and gender identity. An example of this is AMAB (Assigned Male at Birth). [2]
• 1 Terminology and Usage
• 3 Recognition of Intersex or Other
• 4 Assigned Sexes
• 5 Resources

Terminology and Usage

Due to the definition of gender identity being a social/psychological aspect rather than a physical one (body sex), AGAB can be a potentially confusing concept. Historically, AGAB was designed with gender's secondary definition in mind - where gender is a synonym of body sex. [10] Whilst the definition of gender has changed over the years, AGAB as a concept has remained primarily the same. Despite the linguistic conflict, it is officially understood to refer to one's body sex, as that is how one's AGAB is determined. [1] Many English birth certificates use the term body sex for one's gender assignment, however whilst ASAB may be more linguistically correct in terms of definition, AGAB is still far more commonly used.

Individuals whose gender identity matches their birth assignment are referred to as cisgender , while individuals who have a gender identity that differs from their assigned gender may identify as transgender . [11] The difference or relationship between one's gender identity and assigned birth is referred to as one's gender modality .

Gender assignment as a clinical definition was historically referred to as natal male/female. This terminology was changed with the publishing of the the DSM-5-TR (Diagnostic and Statistical Manual of Mental Disorders 5 Text Revision) in 2022, instead opting to use "individual assigned sex/gender at birth". [12] However, AGAB has existed earlier than 2022 and widely used amongst queer communities before its official presence in the DSM. [11]

Originally it was referred to as Sex/Gender Assigned At Birth (SAAB), and its usage traces back to the early 2000s. [13] Its variations also appeared in a similar timeframe, including CAGAB. [14] [15] [16]

The first appearances of AGAB are unknown, but it's been allegedly reported as appropriated from the intersex community. [17] Intersex individuals would use AGAB specifically in cases where an intersex individual is assigned a sex/gender other than intersex. This is reasoned with the notion that the definition of assigned refers to the medical reassignment often prescribed to intersex infants, which differs to the literary recording of one's sex. In a letter to the editor of Times-Call, Susana wrote:

Such people are often, unfortunately, “assigned” a sex (sometimes incorrectly) by doctors who perform a sex assignment surgery on the unconsenting child, to make their genitalia more closely resemble standard female or male genitals. This does not happen to non-intersex people, and it is not accurate to describe women or men as having been “assigned” a sex, when in actuality, their biological sex was simply observed and written down at birth. [17]

However this exclusivity has mostly been lost throughout the years, most likely due to the vague definition of assignment , that being "to designate or set (something) aside for a specific purpose"; as per linguistic manner, a recording of the birth sex (regardless of medical intervention) still meets the definition of an assignment. [18]

Recognition of Intersex or Other

Many countries do not legally recognize intersex or indeterminate as a valid record, and do not allow their documentation on birth certificates, passports, or other forms of identification. However some countries do allow the record and identification of intersex, including the correction of certificates for those that later discovered they were intersex. The amount of regions that have begun to recognize intersex classification have been steadily growing over the past few decades.

In 2016, Sara Kelly Keenan was the first US citizen to receive a birth certificate marking one's assigned sex as intersex. [19] [20] Most Australians have been able to correct their birth certificates since 2009, or in some cases remove the sex field from their birth certificate entirely. [21] In 2013, German began to allow an indeterminate sex option on birth certificates. [22] In 2018, Alex Juergen became the first Austrian to receive an intersex marked birth certificate. [23] In 2016, Canadian transgender parent Kori Doty opted to not record their newborn's sex at all. [24]

Some activists have taken to the idea of removing the sex on birth certificates altogether. [25]

Dr Fiona Kelly, a law school professor, and Hannah Robert, a lecturer in law, wrote of the benefits of removing the assigned sex from one's birth certificate:

Having a gender identity that does not match the sex designation on a birth certificate can create confusion and potentially expose people to discrimination when an identity document is requested, such as when they register at a school or university or apply for a passport. ... Removing sex from birth certificates would also eliminate the need for the parents of an intersex child to choose a sex for their baby to be publicly recorded. This can be a highly difficult and emotional decision for parents and, in some instances, will not reflect the child’s understanding of their gender later on. Leaving the birth certificate blank allows the child to make that decision once they have the knowledge and maturity to confirm their gender identity. " [25]

Assigned Sexes

• ↑ 1.0 1.1 "Birth Assignment". translanguageprimer, https://translanguageprimer.com/birth-assignment/ . Accessed on 19 Jun, 2023.
• ↑ 2.0 2.1 "Glossary". Digital Transgender Archive, https://www.digitaltransgenderarchive.net/learn/glossary . Accessed on 21 Jun, 2023.
• ↑ "Birth certificate (Australian)". Unique Student Identifier, 14 Jun, 2023, https://www.usi.gov.au/students/identification/australian-birth-certificate .
• ↑ Raveenthiran V. Neonatal Sex Assignment in Disorders of Sex Development: A Philosophical Introspection. J Neonatal Surg. 2017 Aug 10;6(3):58. doi: 10.21699/jns.v6i3.604. PMID: 28920018; PMCID: PMC5593477.
• ↑ "Glossary of Terms: Transgender". GLAAD, https://glaad.org/reference/trans-terms/ . Accessed on 19 Jun, 2023.
• ↑ "LGBTQ+ Terminology / Vocabulary Primer". NewYork-Presbyterian, https://www.nyp.org/documents/pps/cultural-competency/Understanding%20Disparities%20-%20LGBTQ%20Terminology.pdf . Accessed on 21 Jun, 2023.
• ↑ "CAGAB". The Trans Language Primer, https://translanguageprimer.com/cagab/ . Accessed on 21 Jun, 2023.
• ↑ 8.0 8.1 8.2 8.3 coded-reality. "October 26: Intersex Awareness Day". Tumblr, 2020, https://coded-reality.tumblr.com/post/188611961035/october-26-intersex-awareness-day .
• ↑ 9.0 9.1 9.2 nonbinary-support. "Hey! I'm intersex.". Tumblr, 2016, https://nonbinary-support.tumblr.com/post/131461402043/hey-im-intersex-do-i-need-to-use-agab-language .
• ↑ Zhu, Handwiki. "Gender." Encyclopedia . Web. 07 November, 2022.
• ↑ 11.0 11.1 "Understanding Gender Identities". The Trevor Project, 23 Aug, 2021, https://www.thetrevorproject.org/resources/article/understanding-gender-identities/ .
• ↑ First MB, Yousif LH, Clarke DE, Wang PS, Gogtay N, Appelbaum PS. DSM-5-TR: overview of what's new and what's changed. World Psychiatry. 2022 Jun;21(2):218-219. doi: 10.1002/wps.20989. PMID: 35524596; PMCID: PMC9077590.
• ↑ "Intro to Understanding Sex, Gender and the Spectrum". kyberia, 21 Apr, 2007, https://kyberia.sk/id/3069259 .
• ↑ Bazant, Micah. "Trans Etiquette/Respect/Support 101". Transtorah, 2011, http://www.transtorah.org/PDFs/Trans_Etiquette_101.pdf .
• ↑ destroyedforcomfort. "AMAB/AFAB vs . CAMAB/CAFAB". Tumblr, 2013, https://destroyedforcomfort.tumblr.com/post/32011963208/amabafab-vs-camabcafab .
• ↑ "Transsexual". TVTropes, https://archive.md/dZncK#selection-4277.1-4401.19 . Archived on 30 Aug, 2017.
• ↑ 17.0 17.1 Santamaria, Susana. "‘Assigned at birth’ appropriated from the intersex community". Times-Call, 6 Feb, 2021, https://www.timescall.com/2021/02/06/letters-sexual-assignment/?fbclid=IwAR18338gF1mWlnVucksTF6R3MulLMQzltg4IT0JFNfla0STJOr6J7eUfNsI .
• ↑ "assign - transcription, translation and pronunciation online". myefe, https://myefe.com/transcription-pronunciation/assign#:~:text=designate%20or%20set%20(something)%20aside%20for%20a%20specific%20purpose .. Accessed on 22 Jun, 2023.
• ↑ 19.0 19.1 O'Hara, Mary Emily. "Nation's First Known Intersex Birth Certificate Issued in NYC". NBC News, 30 Dec, 2016, https://www.nbcnews.com/feature/nbc-out/nation-s-first-known-intersex-birth-certificate-issued-nyc-n701186 .
• ↑ Segal, Corinne. "Nation’s first known ‘intersex’ birth certificate issued in New York City". PBS News Hour, 5 Jan, 2017, https://www.pbs.org/newshour/nation/new-york-city-issues-nations-first-birth-certificate-marked-intersex#:~:text=Meanwhile%2C%20Keenan%20reached%20out%20to%20the%20New%20York%20City%20Health%20Department%2C%20who%20issues%20birth%20certificates%2C%20to%20request%20a%20change%20to%20the%20sex%20listed%20on%20her%20birth%20certificate ..
• ↑ Carpenter, Morgan. "On intersex birth registrations". Intersex Human Rights Australia, 13 Nov, 2009, https://ihra.org.au/4856/on-birth-registrations/ .
• ↑ Muller, Natalie. "Third sex". DW, 1 Nov, 2013, https://www.dw.com/en/third-sex-option-on-birth-certificates/a-17193869 .
• ↑ Savage, Rachael. Anarte, Enrique. "Austria issues first intersex birth certificate after four-year battle". Reuters, 17 Jul, 2020, https://www.reuters.com/article/us-austria-lgbt-rights-trfn-idUSKCN24H33M .
• ↑ 24.0 24.1 Koenig, Ronnie. "Transgender parent explains why they are raising baby without an assigned gender". Today, 18 Jul, 2017, https://www.today.com/parents/transgender-parent-leaves-their-baby-s-gender-unassigned-t113796 .
• ↑ 25.0 25.1 Dr Kelly, Fiona. "Removing sex from birth certificates". La Trobe University, Robert, Hannah, 29 Oct, 2018, https://www.latrobe.edu.au/news/articles/2018/opinion/removing-sex-from-birth-certificates .
• ↑ "AFAB". Merriam-Webster, https://www.merriam-webster.com/dictionary/AFAB . Accessed on 19 Jun, 2023.
• ↑ beyond-mogai-pride-flags. "DFAB Flag". Tumblr, 15 Oct, 2020, https://archive.md/2022.02.12-070010/https://beyond-mogai-pride-flags.tumblr.com/post/632047659950194688/dfab-flag . Archived on 12 Feb, 2022.
• ↑ themogaidragon. "AIAB". Tumblr, 17 Sep, 2021, https://themogaidragon.tumblr.com/post/662581001970728960/aiab .
• ↑ "AMAB". Merriam-Webster, https://www.merriam-webster.com/dictionary/AMAB . Accessed on 19 Jun, 2023.
• ↑ beyond-mogai-pride-flags. "DMAB Flag". Tumblr, 15 Oct, 2020, https://archive.md/2022.02.12-084755/https://beyond-mogai-pride-flags.tumblr.com/post/632047211246764032/dmab-flag . Archived on 12 Feb, 2022.
• ↑ beyond-mogai-pride-flags. "AXAB Pride Flag". Tumblr, 9 Oct, 2020, https://archive.md/2022.02.12-094909/https://beyond-mogai-pride-flags.tumblr.com/post/631548226993012736/axab-pride-flag . Archived on 12 Feb, 2022.
• ↑ 32.0 32.1 interarchival. "fafab + famab". Tumblr, 27 Dec, 2021, https://web.archive.org/web/20230107041309/https://interarchival.tumblr.com/post/671776339598196736/fafab-famab . Archived on 7 Jan, 2023.
• ↑ 33.0 33.1 https://interarchival.tumblr.com/post/671769367452778496/iafab-iamab [Dead Link]
• ↑ beyond-mogai-pride-flags. "UAB Pride Flag". Tumblr, 3 Mar, 2019, http://archive.today/2022.04.20-012243/https://beyond-mogai-pride-flags.tumblr.com/post/183189528435/uab-pride-flag . Archived on 20 Apr, 2022.

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Ambiguous genitalia and disorders of sexual differentiation.

Khawar T. Mehmood ; Rebecca M. Rentea .

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Last Update: August 28, 2023 .

• Continuing Education Activity

Infants born with a disorder of sex development (DSD) prompt multiple medical, surgical, ethical, psychosocial, and physical issues for patients and their parents. The previous terms, such as intersex, hermaphroditism, pseudohermaphroditism, etc., are outdated and are replaced by the term disorders of sexual development (DSD). This activity reviews the evaluation and management of infants born with DSD and highlights the interprofessional team's role in the management of patients with this condition.

• Describe the pathophysiology of disorders of sexual development.
• Explain the common physical findings in disorders of sexual development.
• Review the management considerations of patients with disorders of sexual development.
• Outline the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients with disorders of sexual development.
• Introduction

The birth of an infant with ambiguous genitalia generates difficult multiple medical, surgical, ethical, psychosocial, and physical issues for patients and their parents. Phenotypic sex results from the differentiation of internal ducts and external genitalia under the influence of hormones and other additional factors. When discordance occurs among three processes (chromosomal, gonadal, phenotypic sex determination), a DSD is the result. 

Terminology, such as hermaphrodite, pseudo-hermaphrodite, and intersex, are considered to be pejorative and dated. These terms have been replaced by the term disorders of sexual development (DSD) by the consensus statement on the management of intersex disorders. [1] [2]  Disorders of sexual development are defined as congenital conditions characterized by atypical development of chromosomal, gonadal, or anatomic sex. [3]

Normal sexual development in utero is dependent upon a precise and coordinated spatiotemporal sequence of various activating and repressing factors. [4]  Any deviations from the usual pattern of differentiation can present as DSDs. Two distinct processes occur in normal sexual development. The first of which is sex determination, in which the bi-potential gonads are induced to form either the male testes or the female ovaries. Secondarily, the newly formed gonads secrete hormones to modulate the formation of internal and external genitalia. [5]

The phenotypic manifestation of DSDs are diverse and can include; bilateral undescended testes, severe hypospadias (scrotal or perineal), clitoromegaly, a fusion of posterior labial folds, female external genitalia with palpable gonad, discordant genitalia, and sex chromosomes. The inclusion of disorders in which there is no genital/gonadal discordance like Turner syndrome, Klinefelter syndrome, simple hypospadias remains controversial.

Regardless of presentation or severity, individuals require an interprofessional approach that is warranted to improve the quality of life and achieve the best possible outcomes.

Sexual development in mammals occurs in two sequential stages: the initial phase of sex determination followed by sex differentiation. [5]  Sex determination is guided by the complement of sex chromosomes inherited at conception. [6]  The inheritance of the Y chromosome and the subsequent expression of the SRY gene drives the bipotential gonad toward differentiation into male-specific testes. [6] In contrast, the absence of the Y chromosome results in the development of the female-specific ovary. The second stage of sex differentiation is characterized by the secretion of certain hormones and other factors by the differentiated gonad, which guides the internal and external genital development and maturation. [7]  The secretion of testosterone and anti-mullerian factor by the Leydig and Sertoli cells, respectively, cause the development of male internal organs and reciprocal regression of female sex organs. The absence of these hormones leads to the formation of the female sexual organs.

A multitude of genes plays an important role in orchestrating this complex sequence of events. A detailed review of these genes is beyond the scope of this article. However, an overview of the most important genetic factors is provided below.

1. SRY gene: the sex-determining region of the Y chromosome is the chief regulator of male sex differentiation; expression causes translation of SRY protein, which mediated testicular development. [8]

2.SOX9 gene: expression of this gene follows the SRY gene and is responsible for the differentiation of Sertoli cells.

3. NR5A1/SF-1: The steroidogenic factor gene codes an important transcription factor involved in male development and steroid biosynthesis. [9] [10]

4. DHH gene: The desert hedgehog gene plays a role in testicular differentiation. [11]

5. DAX/NROB1: Considered as an anti testis factor up-regulated in the ovary.

6.WT1: Codes a transcription factor involved in renal and gonadal development, mutation results in various congenital syndromes of abnormal genitourinary development.

7. Wnt4 and Wnt 7a: Wnt 4 suppresses male sexual differentiation and ovarian androgen production. [12]

A mutation in any of these above genes may lead to the development of DSD. A loss of genes involved in male sexual development can lead to an undervirilized male or 46 XY with a female phenotype.

A finely balanced hormonal milieu is required for normal sexual development; testosterone is necessary to stabilize the Wolffian ducts, while secretion of anti-Mullerian factors is essential for the regression of Mullerian ducts.

The male external genitalia requires the presence of dihydrotestosterone for normal phenotypic development. The deficiency of this hormone or resistance may lead to undervirilized genitalia. Exposure of female genitalia to excess androgens leads to virilization, which may be due to excess production or exogenous exposure.

Aromatase deficiency is characterized by reduced levels of estrogen and increased levels of testosterone. This is seen in 46,XX females with ambiguous genitalia. They often have normal internal reproductive organs.

• Epidemiology

The incidence of a child with a disorder of sexual development (DSD) is approximately 1 in 1000 to 4500 live births. [13] [1]  The most frequently occurring etiology was congenital adrenal hyperplasia (CAH), followed by androgen insensitivity and mixed gonadal dysgenesis.

• Pathophysiology

To fully appreciate the diversity and complexity of disorders with sexual development, the complex embryological process requires review. The following paragraphs will outline the basics of sexual development and hopefully tie in the important etiologies.

During early fetal development, males and females share a common anlage. This phase lasts for up to 7 weeks, after which development proceeds down two distinct genetic pathways.

Inheritance of the 46 XY chromosome leads to the expression of the SRY gene located on the Y chromosome. [14]  The SRY can be considered as the control switch for male sex development; its appearance triggering significant downstream effects that eventually result in the formation of male-specific gonads. [15]  Definitive missense mutations provide evidence of this fact in this gene leading to 46, XY gonadal dysgenesis. [16]  Whereas its translocation and expression in individuals with 46 XX result in male or ambiguous genitalia.

The second most crucial gene in male sexual determination encodes the transcription factor SOX9. Mutation in this all-important gene is responsible for the autosomal dominant campomelic dysplasia characterized by 46XY genotype and ambiguous or female external genitalia. [17] Furthermore, duplication of this gene results in male or ambiguous genitalia in a 46 XX infant.

Mutations in various other transcription factor encoding genes that promote testicular differentiation have also been implicated in aberrant sexual development. The NS5A1 (also known as steroidogenic factor 1 SF-1 gene) is a key regulator of testicular development along with the formation of the hypothalamic-pituitary-adrenal axis. [18] Mutation results in gonadal and adrenal dysgenesis in individuals with 46 XY genotypes and female external genitalia. [19]

Similarly, mutations in other essential genes involved in male development such as DHH, NROB1, GATA4, ZFMP2 all lead to 46XY individuals having female or ambiguous genitalia.

Once the testes have developed, the Sertoli cells secrete the anti-Mullerian factor, which causes involution of paramesonephric duct (Mullerian), and Leydig cells produce testosterone, which stabilized mesonephric (Wolffian) ducts. Deficiency of testosterone due to a biosynthetic defect such as enzyme deficiencies like cholesterol desmolase (CYP11A1), 3 beta-hydroxysteroid dehydrogenase (HSD3B2), 17 alpha-hydroxylase (CYP17), P450 oxidoreductase (POR), among others can present with ambiguous genitalia or micropenis along with symptoms of adrenal insufficiency. Similar female phenotypes can be seen in the absence of adrenal receptor deficiency, which is characteristic of androgen insensitivity syndromes. Deficiency of anti-Mullerian hormone or its receptor presents as male external genitalia with cryptorchidism and persistent Mullerian ducts. [20]

Dihydrotestosterone controls the external genital development, characterized by phallic enlargement and fusion of urogenital folds to form the penile urethra. The labio-scrotal fold fusion to form the scrotum is governed by the enzyme 5 alpha-reductase type 2.  The deficiency of these enzymes leads to undervirilized males with micropenis or males with ambiguous genitalia with normally functioning testes. [21]

In contrast, individuals with 46 XX genotypes lack the SRY gene, leading to the progression of bipotential gonad towards ovarian development. However, contrary to previous beliefs, ovarian development is not merely a passive default pathway. [22] ) Initially, there is increased expression of WNT4 and RSPO1, which upregulate and stabilize the beta-catenin transcription factor, which suppresses the male-specific SOX gene. Maintainance of the ovarian phenotype is promoted by the expression of the FoxL2 gene and the estrogen receptors. Mutation in this gene results in 46, XX gonadal dysgenesis with BPES (blepharophimosis, ptosis, and epicanthus inversus syndrome). [23]  Aromatase deficiency results from autosomal recessive inheritance of mutations in the CYP19A1 gene.

The absence of testosterone leads to the involution of Wolffian ducts and Mullerian duct differentiate into Fallopian tubes and uterus due to the absence of anti-Mullerian factors.

External genitalia develops into the female phenotype due to the absence of androgens. Disorders of enzyme biosynthesis, which shunt steroid precursors towards formation androgens, lead to virilization of female external genitalia. The most frequent of these disorders are due to a deficiency of 21 alpha-hydroxylase, causing the classical variant of congenital adrenal hyperplasia characterized by female virilization and potential salt-wasting crises in neonates. Other less severe forms of CAH arise due to deficiencies in hydroxysteroid dehydrogenase, 11 beta-hydroxylase, and p450 oxidoreductase. Exogenous androgen exposure or maternal aromatase deficiency also gives rise to a fetus with virilized genitalia.

In summary, any deviation from the intricate sequence of sexual development may give rise to disorders of sexual development.

• History and Physical

As with most diseases, a careful history and thorough examination are crucial for making an early diagnosis. A newborn with bilateral non-palpable testes or a unilateral impalpable testis and severe hypospadias should be regarded as having a DSD until proven otherwise, whether or not the genitalia grossly appears ambiguous. The incidence of DSD in individuals born with hypospadias and cryptorchidism ranges between 17% and 50%. 

History should include any maternal exposure to androgens (e.g., danazol ) during the current pregnancy and any history of maternal virilization during pregnancy. [24] [25]  Maternal virilization can be caused by a deficiency of placental aromatase as well as by luteomas of pregnancy. A report of maternal ingestion of exogenous maternal hormones (such as those used in assisted reproductive techniques) and maternal use of oral contraceptives or soy products during pregnancy. Family history is essential, including those with urologic abnormalities, precocious puberty, amenorrhea, infertility, or neonatal deaths.  History or family history of consanguinity among partners increases the likelihood of various autosomal recessive causes of ambiguous genitalia (e.g., congenital adrenal hyperplasia). History of previous neonatal deaths may also provide a clue towards CAH. Siblings with primary amenorrhea and XY karyotype are seen in patients with the X-linked androgen insensitivity syndrome. [26]  

A careful and detailed physical evaluation is paramount for an accurate diagnosis. An examination should be focused on inspection and palpation of genitalia. The child should be examined in a warm room, supine and in the frog-leg position, with completely free moving legs. This allows for the testicle(s) that may not have descended to be palpated along their course: the inguinal canal, the superficial inguinal pouch, the upper scrotum, or rarely the perineal, femoral, or contralateral scrotal regions. 

Documentation of the size of the penis or clitoris, number on perineal openings, presence of testes in labial or inguinal regions should be considered.

The average stretched penile length in a term male infant is between 2.8 to 4.2 cm. [9]  Though the penile length is dependent upon fetal gestational age as well as race. Microphallus itself is not a marker of disorder of sexual development. Typical findings include bilateral non-palpable testes, scrotal or perineal hypospadias, and hypospadias with unpalpable gonad.

The normal clitoral length in full-term female infants is 3.3 to 6.5 mm, with clitoromegaly defined as length greater than 9 mm. Other findings include fused labial folds, inguinal masses, and urogenital sinus formation.

A uterus can be palpated on a digital rectal examination as an anterior midline cord-like structure. 

Other non-genital abnormalities and dysmorphic features should be documented. For example, patients with Smith-Lemli-Opitz syndrome have ambiguous genitalia and microcephaly, posteriorly rotated low set ears, and fusion of second and third toes. [27]  Additional findings include a short, broad neck, widely spaced nipples, and aniridia. 

The initial evaluation should include karyotyping, which is usually performed on peripheral leukocytes. Depending on karyotype, individuals are categorized into three main types 46XX DSD, 46 XY DSD, and mixed chromosome DSD. [2]

Another critical test is the fluorescent in situ hybridization (FISH) for the SRY gene. This gene is the master regulator of male sex development. The absence of the SRY gene in a 46XY karyotype indicates deletion and can result in DSD ranging from ambiguous genitalia to sex reversal. [15] [8]

Investigations for congenital adrenal hyperplasia (CAH) should be prioritized as a delayed diagnosis can lead to salt-wasting and high morbidity and mortality. Measuring 17hydroxyprogesterone should be performed in all neonates with atypical genitalia and absent inguinal swellings to exclude classical CAH. Measurement of dehydroepiandrosterone (DHEA), 17-hydroxypregnenolone, and 11-deoxycortisol will help in the diagnosis of other causes of CAH. [28]

Other tests include the analysis of testosterone after stimulation and measuring gonadotrophins.

Imaging modalities such as ultrasound and MRI help delineate the anatomy and visualize gonads, uterus, and vagina. Vaginoscopy is also an essential modality for accurate visualization of vaginal anatomy.

The results of the karyotype and SRY gene further guide the management.

Individuals with 46 XX Disorders of Sexual Development

In individuals with ambiguous genitalia and 46 XX, FISH for SRY determines further investigations. Individuals with SRY positivity have SRY gene translocation causing ambiguous genitals.

Those with SRY negativity can be evaluated by measuring the concentration of 17 hydroxyprogesterone. Elevated levels point towards congenital adrenal hyperplasia as a cause for virilization of the female fetus. Though the most common deficiency for CAH is 21 alpha-hydroxylase, other enzyme deficiencies such as 11 beta-hydroxylase, 3 beta dehydrogenase, and P450 oxidoreductase should be considered. These less common causes for CAH can be distinguished based on the measurement of 17-hydroxypregnenolone, cortisol, dehydroepiandrosterone, and 11 deoxycortisol.

Patients with aromatase deficiency have elevated levels of FSH and undetectable serum estradiol.

Individuals with normal levels of 17 hydroxy progesterone should then undergo a pelvic ultrasound to ascertain the internal anatomy. Those with normal internal female anatomy are likely exposed to androgens during gestation. The androgens can be exogenous, e.g., danazol, synthetic progestins, etc., or can be endogenous, e.g., luteomas of pregnancy, Placental aromatase deficiency.

Patients in whom ultrasound reveals abnormal female internal organs are then tested for anti-Mullerian hormone levels and testosterone levels, and human chorionic gonadotrophin. Elevated levels are suggestive of ovotesticular DSD.

Individuals with 46 XY and Disorders of Sexual Development

In individuals with 46 XY karyotype and ambiguous genitalia, FISH for the SRY gene guides further investigations. Individuals with the absence of the SRY gene are due to deletion.

Those with SRY positivity are more difficult to evaluate due to a plethora of diverse etiologies. Congenital adrenal hyperplasia can also lead to an undervirilized 46XY fetus. The etiologies include deficiency of 17 alpha-hydroxylase, 3 beta-hydroxysteroid dehydrogenase, steroid acute regulatory protein, P450 oxidoreductase, P450 side-chain cleaving enzyme. Measurement of 17-hydroxypregnenolone, deoxycorticosterone, and DHEA serve to differentiate among these conditions. To confirm a deficiency of 17 alpha-hydroxylase or 3 beta-hydroxysteroid dehydrogenase, an ACTH stimulation test to measure the steroid precursors are required.

In other individuals, the presence of testicular tissue can be ascertained by either performing ultrasound or measuring the concentration of anti-Mullerian hormone (AMH), which serves as a marker of testicular tissue. In patients with low AMH, gonadal dysgenesis, testicular regression syndrome, vanishing testicular syndrome, or persistent Mullerian duct syndrome are likely causes.

Patients have a normal testicular reserve as evidenced by normal levels of anti-Mullerian hormone and the subjected to beta chorionic gonadotrophin stimulation to differentiate between abnormal androgen synthesis versus abnormal androgen response. Beta HCG is administered, followed by measurement of testosterone, dihydrotestosterone (DHT), and androstenedione.

Patients who have normal responses to beta HCG stimulation as evidenced by 4 fold increase in testosterone by day 6, testosterone to DHT ratio of less than 10 to 1, and testosterone to androstenedione greater than 0.8, may have LH receptor defects, 5 alpha-reductase deficiency, or 17 hydroxysteroid dehydrogenase deficiency.

Individuals with normal response to beta HCG likely have androgen insensitivity syndrome, AMH receptor defect, or exposure to endocrine disruptors such as phenytoin.

Individuals with Sex Chromosome DSD

These are individuals who on karyotyping are found to have 45 X/46 XY mosaicism or 46 XX/46XY mosaic. Individuals without atypical genitalia such as Turner syndrome or Klinefelter syndrome are also included in this subgroup.

• Treatment / Management

The management of individuals with disorders of sexual development can be complex. Psychosexual development is dependent on factors such as societal and cultural norms, in utero exposure to androgen, genetic differences, and familial dynamics. The previous management guidelines of early genital surgery based on expected fertility outcomes and phallic functionality are being challenged due to evolving evidence. A need to move away from physician-directed early gender assignment surgeries is warranted because of poor long-term outcomes. [29] [30] [31]

The management should be focused on three main domains; initial stabilization, accurate diagnosis, and decisions on the gender of rearing and planning of surgical intervention and hormonal treatment.

Congenital adrenal hyperplasia, which is the most common cause of ambiguous genitalia, can present as life-threatening salt-wasting crises. Prompt diagnosis and treatment with glucocorticoids should be instituted.

Accurate diagnosis is essential; in some cases, diagnosis may be obvious; however, it is prudent to transfer cases to a center experienced in the management of DSDs. A frank and honest discussion with the parents regarding the delay of gender assignment until the diagnosis is clear is warranted.

The decision for gender assignment should be made upon the best available evidence and considerations of such as type of DSD, prenatal androgen exposure, the possibility of fertility and sexual functionality, and psychosocial factors. [32] [33] [34] . There are strongly differing viewpoints regarding the timing of gender assignment. The first is to assign complete genital reconstruction after birth to avoid internal conflicts with the patient or external societal conflicts as the child develops. The opposing viewpoint is that gender assignment is a shared decision that the affected individual participates in during puberty- essentially, physicians and family cannot predict future gender identity or sexual orientation. Three considerations in the discussion of gender assignment include the functional and anatomic ability of the genitalia (size of the phallus or vagina, fertility potential), the cause of the DSD, and the values and desires of the family. 

The basic principles of surgery are to ensure the best cosmetic results, preserve sexual functioning, preserve fertility if possible, and decrease the risk of malignancy in the dysgenetic gonad. Deferring surgery is often advocated until the child is old enough to confirm their gender identity.

Surgical management of certain common DSDs is listed below.

Congenital adrenal hyperplasia 46XX: The management of individuals is straightforward. Those up to Prader stage 1 to 4 virilizations are recommended for a female gender of rearing. However, for individuals with severe virilization and those in whom the diagnosis is delayed, male rearing should be considered. Surgery is aimed to restore the vaginal and urethral position and to correct the fistula between the vagina and urogenital sinus. Preservation of clitoral function is another important consideration. [35] [36]

Gonadal dysgenesis 45X/46XY mosaic: These individuals have virilization, a Y chromosome, and exposure to androgens in utero. Therefore, the male gender of rearing is recommended. A hypospadias correction and removal of streak gonad is recommended. These individuals are at increased risk of malignancy. Therefore post-puberty biopsy and gonadectomy are recommended if the biopsy is positive. [37]

46 XY DSD: For individuals with a deficiency of 17 beta-hydroxy dehydrogenase or deficiency of 5 alpha-reductase, a male gender of rearing is recommended. Hormonal stimulation for phallic growth followed by hypospadias correction and orchidopexy is advocated.

Certain DSDs predispose to an increased risk of gonadal cancer. Mixed gonadal dysgenesis and partial androgen insensitivity are associated with higher oncologic risk. The timing of gonadectomy depends on the risk, gender of rearing, and functionality of the gonad. Individuals to be raised as females removal is advocated at the time of genitoplasty. For males, orchidopexy and biopsy after puberty are recommended. Streak gonads are preferably removed as early as possible.

In addition, psychosocial support and education should be provided to both parents as well as children with DSD.

• Differential Diagnosis

The diagnosis of DSD is often suspected following external evaluation of the genital area. Additional diagnoses encountered in the differential diagnosis include cloaca, urogenital sinus, rectovaginal fistula, various congenital duplications such as caudal duplication. [38]  Certain conditions such as cryptorchid testes, penile hypospadias, micropenis, etc., mimic DSD; however, unlike true DSD, there is are no inconsistencies between karyotype and genitalia.

Though the prognosis is good, the disease is associated with considerable psychosocial morbidity. Additionally, associated medical and surgical conditions contribute to the overall prognosis.

• Complications

The most severe complication can arise due to neonatal salt wasting in congenital adrenal hyperplasia (CAH). Early diagnosis is crucial to prevent neonatal morbidity and mortality. Individuals with dysgenetic gonads are at risk of developing gonadal tumors, especially those with a Y chromosome in their karyotype. Surgery and treatment may not be able to achieve satisfactory sexual functionality, and fertility remains suboptimal.

• Consultations

An interprofessional dedicated clinical practice is often required for optimal management. The group of providers present in the interprofessional care of children with DSD includes a pediatric surgeon with expertise in DSD, pediatric urology, pediatric gynecologist, endocrinologist, and psychologist. 

• Deterrence and Patient Education

A holistic and interprofessional approach is required when dealing with a patient with a disorder of sex development (DSD). A comprehensive discussion regarding specific outcomes and delaying gender assignment until the diagnosis is confirmed is advocated. Delayed surgery is now recommended to decrease the incidence of gender dysphoria and improve functional outcomes.

• Pearls and Other Issues

The term disorder of sex development or disorder of sexual development (DSD) has replaced outdated terms such as 'intersex' or 'ambiguous genitalia.'

The differential diagnosis can be overwhelming, so a systematic interprofessional approach is paramount. 

A disorder of sex development(DSD) is suspected in any infant who has the physical examination findings of bilateral nonpalpable undescended testes or hypospadias with unilateral undescended testis. 

Three essential details on the evaluation of a newborn with suspected DSD are ascertaining if there is a patent anus on assessment, are the genitalia symmetric or asymmetric, and does the infant has a XX or XY karyotype? 

Up to one-half of males with hypospadias and cryptorchidism will have a DSD. 

The most important initial finding on physical examination is the presence and number of gonads. 

A uterus may be palpable on digital rectal examination. 

The newborn period requires a karyotype and laboratory evaluation. 

To summarize DSD evaluation: 

Evaluation Begins with Palpation of the Gonads 

0 gonads palpated (46XX DSD, GD, 46 XY, ovotesticular DSD)

1 gonad palpated (partial GD ovotesticular DSD, 46 XYDSD) 

2 gonads palpated (46 XY DSD Ovotesticular DSD (rare))

The most important aspects of diagnosis and treatment include:  

1. Karyotype evaluation

2. Laboratory evaluation: serum electrolytes, 17-hydroxyprogesterone (17 0H-P), testosterone (T), dihydrotestosterone (DHT), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels

3. Pelvic ultrasound 

4. Possible laparoscopy with gonadal biopsy

Based on Laboratory Values 

1. If 17 OH-P (>2000 ng/dl) and high testosterone with uterus present, then the diagnosis is 46 XX DSD  (CAH). There is further differentiation based on 11 deoxycortisol level and deoxycortisone (DOC)- (if low 11 deoxycortisol and low DOC, then 46XX DSD or 21 alpha-hydroxylase deficiency) (if high 11 deoxycortisol and high DOC, then 11 beta-hydroxylase deficiency) 

2. If normal 17 OH-P  (testosterone increased and uterus seen, and on laparoscopy, with gonadal biopsy, and  there are ovaries 46XX DSD (maternal virilizing syndrome) 

3. If normal 17 OH-P (possible uterus and normal testosterone, perform laparoscopy with gonadal biopsy). If testis, ovary, ovotestis- diagnosis is ovotesticular DSD: 46XX, 46 XX/XY, 45X/46XY. If streak, this is gonadal dysgenesis, either pure 45X, 45X/46XX, 46XX, 45X/46/XY, or partial 45X/46XY, 46XY. 

4. If normal 17 OH-P ( possible uterus and normal testosterone, perform laparoscopy with gonadal biopsy). Two testes, HCG stimulation pre/post, are performed, testosterone/DHT, and DHEA/androstenedione obtained. The diagnosis is 46XY DSD: 46XY, 46XX, 45X/46XY. Consider one of the following diagnoses: 5 alpha-reductase deficiency, androgen insensitivity syndrome (AIS),  steroid deficiency- male CAH, dysgenetic testes, persistent Mullerian duct syndrome (PMDS), and primary testicular failure. 

• Enhancing Healthcare Team Outcomes

An interprofessional approach is required in a tertiary center for dealing with individuals with DSDs. A working liaison with a pediatrician, pediatric surgeon, pediatric endocrinologist, and child psychologist Is required. The patient and their family should be involved in the discussion. As the understanding of this disease and its psychosocial aspects become clear, a more patient-centric approach is advocated.

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Disclosure: Khawar Mehmood declares no relevant financial relationships with ineligible companies.

Disclosure: Rebecca Rentea declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Mehmood KT, Rentea RM. Ambiguous Genitalia and Disorders of Sexual Differentiation. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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