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Differences of sex development: An update
*Corresponding author: Prajnya Ranganath, Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India. prajnyaranganath@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Ranganath P. Differences of sex development: An update. Wadia J Women Child Health. 2025;4:88-95. doi: 10.25259/WJWCH_34_2025
Abstract
The term “differences of sex development (DSDs)” refers to a group of clinically and etiologically heterogeneous congenital conditions wherein the development of chromosomal, gonadal, or anatomic sex is atypical. Disorders associated with ambiguous genitalia as well as those with hypogonadism are included within the umbrella term of DSD. DSDs can occur in isolation or as part of a syndrome with multisystemic involvement. Chromosomal analysis and endocrinology evaluation are essential in every individual suspected to have a DSD. Based on the chromosomal pattern, DSDs are broadly classified as sex chromosome DSDs, 46,XY DSDs, and 46,XX DSDs. Management involves hormonal therapy, management of reproductive issues, genitoplasty for genital ambiguity, and treatment of associated systemic involvement in syndromic patients. Counseling regarding management options can be challenging particularly with respect to decision-making regarding the sex of rearing and should be done by a multidisciplinary team involving a clinical geneticist, an endocrinologist, a genitourinary surgeon, and a psychologist. This review provides an overview of the clinical approach, diagnostic evaluation, management options, and counseling for DSDs.
Keywords
Ambiguous genitalia
Differences of sex development
Hypogonadism
INTRODUCTION
Differences of sex developments (DSDs) are a group of congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. DSD is an umbrella term which includes disorders associated with ambiguous genitalia as well as hypogonadism.[1] When the appearance of the external genitalia is at variance with what is normal for either male or female sex, it is called atypical or ambiguous genitalia.
TERMINOLOGY
Conventionally used epithets such as “intersex,” “sex reversal,” “hermaphroditism,” and “pseudohermaphroditism” are now considered to be demeaning and confusing and are best avoided. The term “disorders of sex development” was considered acceptable until recently, but now the term “differences of sex development” is preferred. Even the commonly used term “ambiguous genitalia” is considered to have a negative connotation, and “atypical genitalia” is preferred instead.[1,2]
PHYSIOLOGY OF SEX DEVELOPMENT AND DIFFERENTIATION
Development of the gonads and genitalia involves a two-step process: the first is sexual determination which involves formation of the testis or ovary from the primitive gonad; and the second is sexual differentiation which involves development of the internal and external genitalia by the action of hormones secreted by the fetal gonads. Gonadal determination begins from around the 6th week of embryonic life, till which time the primordial gonad remains bipotential. In the 46,XY embryo, it is initiated by the sex-determining region Y (SRY) gene (present on chromosome Yp11.2); SRY codes for a transcription factor which activates the testis-forming pathway, which, in turn, triggers expression of SOX9 and other downstream genes such as DMRT1 which lead to formation of the testes. In the 46,XX embryo, absence of SRY leads to non-expression of SOX9 and expression of other genes such as WNT4, RSPO1, and FOXL2 which lead to formation of the ovaries from the bipotential gonads.[1,3]
In the 46,XY embryo, formation of the testes is followed by secretion of testosterone from the Leydig cells of the testes. Testosterone leads to differentiation of the internal genitalia, that is, epididymis, vas deferens, ejaculatory duct, and seminal vesicles from the Wolffian ducts. Testosterone gets converted into dihydrotestosterone (DHT) by the action of the enzyme 5-alpha-reductase and DHT is responsible for the normal male-like virilization of the external genitalia (penis and scrotal sacs). The Sertoli cells of the embryonic testes produce the Müllerian inhibiting substance (MIS) or anti-Müllerian hormone (AMH) which causes regression of the Müllerian duct and non-development of the duct derivatives which form the internal female genitalia.[1,3]
In the 46,XX embryo, absence of testosterone results in nonvirilization leading to normal female-like appearance of the external genitalia (clitoris, labia majora, and labia minora). Absence of MIS leads to development of the internal female genital organs from the Müllerian ducts (uterus, cervix, fallopian tubes, and the upper part of the vagina).[1,3]
CLASSIFICATION AND GENETIC BASIS
One of the most widely used standard classification systems for DSDs is the one given in 2006 by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology.[2-5] As per this classification system, DSDs are classified into three broad categories. These include:
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Sex chromosome DSDs: This category consists of conditions which are associated with anomalies of sex chromosomes, such as:
45,X (Turner syndrome) and variants [e.g., mosaic Turner syndrome (45,X/46,XX), ring chromosome X – 46,X,r(X), and Isochromosome Xq - 46,X,i(Xq)]
47, XXY (Klinefelter syndrome) and variants (e.g., 48,XXXY)
45,X/46,XY (Mixed gonadal dysgenesis)
46,XX/46,XY or 46,XX/47,XXY (which can present as ovotesticular DSD).
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46, XY DSDs: This category includes conditions where the chromosomal analysis shows a normal male chromosomal complement (46,XY) but the gonadal or anatomical sex is atypical. These include:
Disorders of gonadal development – these include complete gonadal dysgenesis (Swyer syndrome), partial gonadal dysgenesis, testicular regression syndrome, and 46,XY ovotesticular DSD. In some individuals with gonadal dysgenesis, pathogenic variants involving the SRY, NR5A1, and WT1 genes may be found, but in a significant proportion of cases, the underlying cause remains unidentified. Majority of affected individuals have isolated gonadal dysgenesis, but in some cases, it may occur as part of a syndrome such as Frasier syndrome, Denys-Drash syndrome, or campomelic dysplasia.
Disorders of androgen synthesis – these conditions are caused by variants in genes related to the steroid biosynthesis pathway which are important for the production of androgen. These include HSD17B3 gene-related 17-beta hydroxysteroid dehydrogenase III deficiency, 3-beta-hydroxysteroid dehydrogenase 2 deficiency (HSD3B2) gene-related congenital adrenal hyperplasias (CAH) with 3-beta-hydroxysteroid dehydrogenase 2 deficiency, and CYP17A1 gene-related CAH with 17-alpha-hydroxylase deficiency. SRD5A2 gene-related deficiency of the enzyme 5-alpha-reductase results in impaired conversion of testosterone to DHT; as DHT is essential for differentiation of the external male genitalia, reduced DHT leads to under-virilization of the external male genitalia.
Disorders of androgen action – these are caused by pathogenic variants in the AR gene which codes for androgen receptors which are essential for the normal development of the male external genitalia. Depending on the impact of the gene variants on the function of the androgen receptors, the androgen insensitivity may be partial or complete, and correspondingly, the phenotype can range from mild under-virilization to female-like external genitalia.
Persistent Müllerian duct syndrome – these autosomal recessive (AR) conditions which manifest only in males (male sex-limited AR disorders) are caused by biallelic pathogenic variants in the AMH or AMHR2 genes.
Unclassified disorders – these include undescended testes/cryptorchidism, hypospadias, or epispadias of unknown origin.
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46, XX DSDs: This subgroup includes conditions where the chromosomal analysis shows a normal female chromosomal complement (46,XX) but the gonadal or anatomical sex is atypical, such as:
Disorders of gonadal development – these include monogenic forms of primary ovarian insufficiency caused by pathogenic variants in genes involved in ovarian development (e.g., NR5A1 and WT1). 46,XX testicular DSD and 46,XY ovotesticular DSD are also included in this subgroup. Around 80% of individuals with 46,XX testicular DSD are SRY positive, and the remaining cases may have copy number variants (CNVs) involving SOX3 or SOX9 genes or heterozygous pathogenic variants in NR5A1 or WT1 genes
Disorders of androgen excess – this subgroup includes the CAH of which the most common is 21-hydroxylase deficiency related CAH caused by biallelic pathogenic variants in the CYP21A2 gene; biallelic pathogenic variants in HSD3B2 and CYP11B1 (11-beta-hydroxylase deficiency) also cause CAH with 46,XX DSD. This subset also includes CYP19A1 gene-related aromatase deficiency, POR gene-related Antley-Bixler syndrome, maternal virilizing tumors (such as luteomas), and iatrogenic causes (such as maternal intake of androgenic drugs).
Unclassified disorders – these include conditions such as Mayer-Rokitansky-Kuster-Hauser syndrome which are associated with abnormal development of Müllerian structures, for which the underlying basis remains unclear.
Ovotesticular DSDs ovotesticular DSD is characterized by the presence of both ovarian and testicular tissue in an individual; these may be present in the same gonad (ovotestis) or one on each side (ovary on one side, testis on other side). Of all cases of ovotesticular DSD, around 30% have sex chromosome anomalies (mosaic 46,XX/46,XY or 46,XX/47,XXY), ~ 60% have a 46,XX karyotype, and ~10% have a 46,XY karyotype. Among the 46,XX ovotesticular DSDs, around ~10% have translocation of a small region of chromosome Y which includes the SRY gene onto an X or other chromosome, and some have low-level mosaicism for 46,XY. In SRY-negative cases of 46,XX ovotesticular DSD, duplication of SOX9 gene or heterozygous variants in NR5A1, WT1, and RSPO1 variants are reported in some cases. Likewise, in 46,XY ovotesticular DSDs, variants in SRY, SOX9, or DMRT1 genes have been found in some cases. However, in a significant proportion of cases of ovotesticular DSDs, the underlying etiology remains unknown.
Malformation syndromes associated with genital anomalies are listed in Table 1.[6]
| S. No. | Disorder | Associated gene | Clinical features | Pattern of inheritance |
|---|---|---|---|---|
| 1. | Aarskog-Scott syndrome | FGD1 | Under-virilized male genitalia; facial dysmorphism (ocular hypertelorism, downslanting palpebral fissures, broad nasal bridge, low set ears, and maxillary hypoplasia); short and broad hands and feet; interdigital webbing; swan neck deformity of fingers; short stature; and intellectual disability | X-linked |
| 2. | Alpha-thalassemia X-linked intellectual disability syndrome | ATRX | Under-virilized male genitalia; facial dysmorphism (coarse facies, microcephaly, telecanthus, short nose, tented upper lip, and thick lips); hypotonia; global developmental delay/intellectual disability; and alpha thalassemia | X-linked |
| 3. | Antley-Bixler syndrome | POR (Cytochrome P450 oxidoreductase deficiency) | Genital anomalies; craniosynostosis; skeletal and joint deformities (radiohumeral synostosis, neonatal fractures, congenital bowing of long bones, joint contractures, arachnodactyly, and clubfeet); facial dysmorphism (mid-face hypoplasia, proptosis, choanal stenosis or atresia, and low-set dysplastic ears); hydrocephalus; and urinary tract anomalies (hydronephrosis and vesicoureteral reflux) | Autosomal recessive |
| 4. | Campomelic dysplasia | SOX9 | Under-virilized male genitalia; skeletal dysplasia (bending of the long bones, small scapulae, vertebral abnormalities, eleven pairs of ribs); cleft palate; and facial dysmorphism (micrognathia, flat facies, and ocular hypertelorism) | Autosomal dominant |
| 5. | Coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies (CHARGE) syndrome | CHD7 | Genital anomalies; ocular colobomas; choanal atresia; ear anomalies including deafness; cardiac defects; and growth retardation, global development delay | Autosomal dominant |
| 6. | Denys-Drash syndrome | WT1 | Gonadal dysgenesis; under-virilized male genitalia; mesangial sclerosis of kidneys; and Wilms tumor | Autosomal dominant |
| 7. | Frasier syndrome | WT1 | Gonadal dysgenesis; under-virilized male genitalia; and focal segmental glomerulosclerosis (FSGS) | Autosomal dominant |
| 8. | Fraser syndrome | FRAS1, FREM2, GRIP1 | Genital anomalies; eye anomalies (cryptophthalmos/microphthalmos/anophthalmos), urinary tract anomalies (renal agenesis, bladder atresia or hypoplasia); cutaneous syndactyly; facial dysmorphism (dysplastic ears, bifid nose, cleft lip/palate, and microglossia); laryngeal stenosis/hypoplasia, cardiac anomalies; gastrointestinal tract anomalies; diaphragmatic hernia; and skeletal anomalies | Autosomal recessive |
| 9. | Robinow syndrome | WNT5A, ROR2 | Genital anomalies; skeletal dysplasia (short stature, mesomelic limb shortening, and brachydactyly); and facial dysmorphism (ocular hypertelorism, frontal bossing, and midface retrusion) | Autosomal dominant (WNT5A)/Autosomal recessive (ROR2) |
| 10. | Smith-Lemli-Opitz syndrome | DHCR7 (7-dehydrocholesterol reductase deficiency) | Under-virilized male genitalia; prenatal and postnatal growth restriction; facial dysmorphism; microcephaly; intracranial anomalies including holoprosencephaly; cleft palate; intellectual disability; and cardiac defects, postaxial polydactyly, and 2-3 syndactyly of the toes. | Autosomal recessive |
| 11. | Wilms tumor- aniridia- genital anomalies-retardation (WAGR) syndrome | Chromosome 11p13 deletion involving PAX6and WT1genes | Genital anomalies; urinary tract anomalies; Wilms tumor; intellectual disability; behavioral abnormalities; and obesity or growth retardation | Usually occurs de novo |
CLINICAL FEATURES
As mentioned above, DSD is an umbrella term which includes disorders associated with hypogonadism as well as conditions with atypical genitalia. DSDs must be considered with any one or more of the following clinical presentations: (i) In the neonatal period: overt genital ambiguity, apparent female genitalia with enlarged clitoris/ posterior labial fusion, apparent male genitalia with bilateral undescended testes/hypospadias/micropenis, or discordance between the genital appearance and the prenatal karyotype (this would be applicable in countries where prenatal sex determination is allowed but not in India); and (ii) in older children/adolescents: previously unrecognized genital ambiguity, inguinal hernia in a girl, delayed or incomplete puberty, primary amenorrhea or virilization in a girl, breast development in a boy, or gross or cyclic hematuria in a boy.[5]
The salient clinical features of individual subgroups of DSDs are listed below.
Sex chromosome DSDs
Numerical abnormalities of the sex chromosomes (X and Y) lead to abnormal gonadal development. Turner syndrome and its variants are associated with streak gonads (hypoplastic or absent ovaries), and Klinefelter syndrome and its variants are associated with small dysgenetic testes. Both conditions are characterized by hypergonadotropic hypogonadism. However, atypical (ambiguous) genitalia are not seen in these two conditions. Individuals with Turner syndrome have normal female external genitalia and individuals with Klinefelter syndrome have male external genitalia. Turner syndrome usually presents with short stature, delayed secondary sexual development, primary amenorrhea, and infertility/sterility; dysmorphic features such as webbing of the neck, increased naevi, increased carrying angle of the elbows (cubitus valgus deformity), shield chest, and wide-spaced nipples, which are loosely termed as “Turner stigmata” may not be present in all affected girls. Klinefelter syndrome mainly presents with azoospermia and infertility. Many but not all affected individuals have delayed/incomplete secondary sexual development. Tall stature and a Marfanoid habitus, small testicular volume, and gynecomastia are other associated clinical features of Klinefelter syndrome. Behavioral anomalies and learning disability may be seen in some. Mixed gonadal dysgenesis, caused by mosaicism of 45,X/46,XY, is associated with abnormal gonads as well as atypical genitalia. The phenotype of the gonads and external genitalia depends on the proportion of 45,X cells; in fact, 45,X/46,XY mosaic individuals with a larger proportion of 45,X cells can present as Turner syndrome. Mixed gonadal dysgenesis can present with an under-virilized male-like phenotype with cryptorchidism, partial testicular dysgenesis, hypospadias, and persistence of Müllerian structures, with a virilized female-like phenotype, or with asymmetrical external and internal genitalia.[1,5]
46,XY DSDs
In this subgroup, disorders which are associated with complete absence of androgen synthesis or action (such as complete gonadal dysgenesis or complete androgen insensitivity) present with female external genitalia, whereas those associated with reduced androgen synthesis and/or action (e.g., partial gonadal dysgenesis, partial androgen insensitivity, disorders of androgen biosynthesis etc.) present with atypical external genitalia/under-virilized male genitalia [Figure 1]. In the former, who are reared as female individuals, the testes may appear in the inguinal region and be mistaken for inguinal hernia. Conditions associated with reduced or absent synthesis and/or action of MIS or AMH such as complete gonadal dysgenesis or mutations in the AMH and AMHR2 genes have persistence of the Müllerian duct derivatives (i.e., presence of fallopian tubes, uterus and cervix, and upper vagina). The DSDs associated with CAH have additional manifestations; HSD3B2 gene-related CAH has salt-wasting; and CYP17A1 gene-related CAH has salt retention and hypertension.[1,5]
- The external genitalia of an individual with 46,XY differences of sex development due to 5-alpha reductase deficiency showing under-virilization, with unfused labioscrotal folds and hypospadias.
46,XX DSDs
Individuals with 46,XX DSDs have varying degrees of virilization ranging from just an enlarged clitoris to almost male-like genitalia with a penis-like phallus and fused labioscrotal folds resembling scrotal sacs. However, the gonads (i.e., ovaries) will not be palpable in the labioscrotal folds in 46,XX DSDs; only in individuals with 46,XX testicular DSDs who have testes, gonads may be palpable. The most common condition in this subgroup is CYP21A2 gene-related CAH which is associated with 21-hydroxylase deficiency. It accounts for 90-95% of 46,XX DSDs and presents with atypical appearance of the external genitalia due to varying degrees of virilization of female genitalia, with normal internal female genitalia. It is also the most common type of CAH accounting for almost 90% of CAH. It leads to hyperpigmentation of the skin may be generalized or may be more prominent in the external genital region [Figure 2] and results from the adrenal insufficiency which leads to increased levels of adrenocorticotropic hormone (ACTH), which, in turn, stimulates melanin production. Salt-losing crises with dyselectrolytemia occur in around 75% of affected individuals. It is important to note that male individuals with 21-hydroxylase deficiency have an equal risk of developing salt-losing crises, although they do not have atypical genitalia; rather, affected males can have isosexual pseudo-precocious puberty. CYP11B1-related CAH is associated with salt retention and hypertension and HSD3B2-related CAH causes salt wasting. It is important to look for features of virilization in the mother of a 46,XX newborn with atypical genitalia, as maternal virilization may be present in conditions such as maternal intake of androgens, maternal androgen-secreting tumors, and placental aromatase deficiency.[1,5]
- The external genitalia of a female neonate with 21-hydroxylase deficiency-related congenital adrenal hyperplasia showing virilization with enlarged clitoris and partially fused labioscrotal folds, and hyperpigmentation.
Ovotesticular DSDs
These can have variable clinical presentations. The external genitalia can range from normal female-like or normal male-like to ambiguous. The internal genitalia can also be variable with presence of both Müllerian derivatives and male internal genitalia. Development of internal genitalia usually corresponds to the ipsilateral gonad (i.e., if there is testis on the right side and ovary on the left side, the internal genitalia can be male-like on the right and female-like on the left). Some individuals develop signs of feminization at puberty and may even have menstrual cycles. Sterility is frequent but ovulation and spermatogenesis have been reported in some affected individuals.
Syndromic DSDs
The systemic manifestations of syndromic DSDs are mentioned in Table 1.[6]
Risk of germ cell tumors
DSDs with Y chromosome, particularly the 46,XY DSDs with gonadal dysgenesis, the mosaic 45,X/46,XY individuals and those with intra-abdominal testes have an increased risk of developing gonadal tumors such as gonadoblastoma and dysgerminoma. This requires prophylactic gonadectomy and surveillance.
EVALUATION
Clinical examination
Evaluation of an individual affected with DSD should be done in a step-wise manner. The first step is a detailed clinical examination, which involves taking a detailed history including antenatal/perinatal/neonatal history, history of systemic manifestations, developmental milestones, family history, and minimum three-generation pedigree, and thorough physical examination including detailed dysmorphology (head-to-toe) evaluation and systemic examination. Examination of the genitalia involves careful inspection, measurement of the phallic size (the stretched length measurement should be taken and compared to normal), checking whether the labioscrotal folds are fused or unfused, and palpation for the gonads (whether palpable or not; if palpable – whether descended or in the inguinal ring, and the size which should preferably be measured with the orchidometer). The Prader scale is an objective scoring of the degree of virilization of the external genitalia; the score ranges from 0 to 6, with 0 indicating normal female genitalia and 6 indicating normal male genitalia. Examination of the genitalia should be done with sensitivity and after obtaining the consent of the patient and/or the parent/guardian.
Investigations
Cytogenetic analysis is an integral component of the diagnostic work-up of an individual with DSD. Most commonly karyotyping is done, but for quick gender assignment in a newborn, sometimes rapid detection methods such as fluorescence in situ hybridization, quantitative fluorescent-polymerase chain reaction (PCR), or multiplex ligation-dependent probe amplification (MLPA) are used to assess the sex chromosomes.
Imaging through abdominopelvic ultrasound and as required, through magnetic resonance imaging is usually done to look for the Müllerian and Wolffian duct structures. Possible adrenal enlargement and associated renal anomalies can also be looked for through abdominal imaging. Ultrasonography of the inguinoscrotal region is done to look for the testes, when they are not palpable in the scrotal sacs (cryptorchidism).
Hormonal assays are done as relevant. Serum follicle-stimulating hormone and luteinizing hormone assays help to differentiate between hypergonadotropic and hypogonadotropic conditions in adolescent and adult individuals presenting with hypogonadism. For suspected 46,XY DSDs, baseline assay followed by post human chorionic gonadotropin (hCG) stimulation assay (on the 4th day following intramuscular injection with hCG) of testosterone and DHT levels are done. In normal individuals, a three-fold elevation of testosterone over baseline is expected following hCG stimulation. Low levels of testosterone/DHT and failure of the testosterone/DHT levels to increase following hCG stimulation indicate that androgen synthesis is defective (either due to gonadal dysgenesis or due to steroid biosynthesis pathway defects). A high testosterone/ DHT ratio indicates a conversion defect due to 5-alpha reductase deficiency. Normal to high testosterone and DHT levels with normal ratio indicate androgen receptor defects.
Evaluation for CAH: CAH and in particular 21-hydroxylase deficiency has to be looked for through serum 17-hydroxy-progesterone assay in all newborns and infants suspected to have 46,XX DSD, because it accounts for around 90–95% of all 46,XX DSD cases, and early detection and pre-symptomatic initiation of treatment can help in avoiding the medical emergency of salt-losing crises in these babies. In the classic form, 17-OH-progesterone is expected to be more than 10,000 ng/dL; however, in the non-classic form, ACTH stimulation may be required to demonstrate increased levels. Serum electrolytes (sodium, potassium, and chloride) have to be monitored, and plasma renin assay is also done to plan the management. Assays for other forms of CAH may be done, for example, serum 11-deoxycortisol and deoxycorticosterone assay for 11β-hydroxylase deficiency after ruling out 21-hydroxylase deficiency in 46,XX DSD; however, these additional assays may not be readily available at all centers.
Molecular genetic testing is recommended for confirmation of all DSDs which are known to have a monogenic cause. DSDs with clearly documented sex chromosomal anomalies do not require molecular genetic testing. The choice of test would depend on the clinical suspicion. It is important to remember that for many DSDs, the underlying remains unknown, and, therefore, molecular testing may be negative for such cases. If the clinical phenotype +/- hormonal profile is suggestive of specific monogenic causes including the syndromic forms, targeted molecular genetic testing for the same can be done through Sanger sequencing or NGS, depending on the size of the gene/number of exons. For evaluating variants in the CYP21A2 gene related to 21-hydroxylase deficiency CAH, selective amplification of the gene (with the long PCR method) followed by sequencing has to be done as the CYP21A2 gene has a pseudogene (to avoid getting the pseudogene sequence in the analysis), and additionally, MLPA has to be done as deletion/ duplication/gene conversion variants are common in the gene. For DSDs where it is difficult to identify a definite monogenic cause clinically, next-generation sequencing-based whole exome sequencing would be the preferred first-line molecular genetic test. To look for CNVs such as those involving SOX9, MLPA or chromosomal microarray may be required depending on the size of the CNVs.[4]
MANAGEMENT
Management of DSDs involves helping affected individuals/ parents to decide about the sex of rearing, genital reconstruction/genitoplasty as required, hormonal therapy as required, surveillance for gonadal malignancies and gonadectomy as relevant, and management of associated complications and systemic manifestations in CAH and the syndromic forms.
Gender assignment
This is a complex issue with important psychological and social implications. Gender should be assigned after the complete diagnostic process and involves a multidisciplinary approach which includes a clinical geneticist, neonatologist/ pediatrician, endocrinologist, gynecologist, psychologist, and pediatric surgeon/urologist. The factors that influence gender assignment include the underlying cause, the extent of virilization of the external genitalia, the functional status of the gonads, the fertility potential, available therapeutic/ surgical options, views of the family, and cultural biases.[7]
Surgical intervention, in particular genitoplasty and gonadectomy, may be required based on the assigned gender and planned sex of rearing. However, the optimal timing for surgery is debatable, with some arguing in favor of early gender assignment and genitoplasty in infancy or early childhood based on the decision of the parents, and some advocating for postponing the time of intervention to adolescence, based on the decision of the individual.
Feminizing genitoplasty for individuals who choose to be females includes reducing the size of the phallus, creating a normal-looking introitus and labia minora and majora, and vaginoplasty to provide an adequate opening. Masculine reconstruction for individuals who choose to be males includes orchiopexy, hypospadias repair, and removal of retained Müllerian duct structures.
Gonadectomy
Germ cell malignancy mainly occurs in DSD cases with a Y-chromosome. For individuals with 46,XY DSDs who opt to be assigned the female gender, it is best to remove the testes to prevent testicular malignancy and virilization at puberty. Individuals with 46,XY DSDs to be raised as males should be kept under surveillance and testicular biopsy may be required for evidence of premalignant lesions such as carcinoma in situ or undifferentiated intra-tubular germ cell neoplasias. Serum markers such as lactate dehydrogenase, beta-hCG, and alpha fetoprotein can be done annually for surveillance of gonadal tumors.
Hormone replacement therapy
Individuals with hypogonadism require hormone replacement therapy to induce and sustain puberty, to induce secondary sexual characteristics and pubertal growth spurt, to optimize bone mineral accumulation, and for psychosocial maturation. Boys with hypogonadism are given intramuscular injections of testosterone for pubertal changes, and testosterone gels or patches are available for virilization of external genitalia. Girls with hypogonadism are given estrogen and progesterone supplementation to induce secondary sexual changes and for menstruation. Growth hormone therapy is given to girls with Turner syndrome for height gain.
Management of 21 hydroxylase deficiency
Glucocorticoid replacement therapy with hydrocortisone has to be given on a regular basis to all individuals with CYP21A2 gene-related CAH; the dose has to be increased during periods of stress. In the salt-wasting form of CAH, salt supplementation and mineralocorticoid therapy with fludrocortisone should also be added. Monitoring for symptoms and signs of salt-losing crises should be done, and prompt supportive therapy should be initiated during salt-wasting episodes. Females virilized at birth may require feminizing genitoplasty and vaginal dilation. Primary prevention of salt-losing crises is possible through universal newborn screening (17-OH-progesterone assay) and early intervention.
GENETIC COUNSELING
It is essential to establish the underlying etiology, wherever possible, to provide accurate and appropriate genetic counseling to the individual/family. Detailed information is provided about the underlying cause of the condition, the prognosis, the management options, the necessary surveillance for anticipated associated complications, and the risk of recurrence in subsequent pregnancies. Prenatal or preimplantation genetic testing for subsequent pregnancies can be offered for disorders with serious systemic complications and is done through targeted mutation analysis in the chorionic villus sample or amniotic fluid, after identifying the exact pathogenic variants in the proband.
Sex chromosome DSDs
These occur sporadically, and the risk of recurrence is not significantly increased over the baseline risk in subsequent pregnancies of the parents of an affected child.
Autosomal recessive disorders
Most of the disorders involving the steroid biosynthesis pathway including 21-hydroxylase deficiency associated CAH, 5-alpha reductase deficiency, persistent Müllerian duct syndrome, and some syndromes such as Smith-Lemli-Opitz syndrome have an AR pattern of inheritance. The risk of recurrence in each subsequent offspring of the affected child’s parents would be 25%; however, the phenotype may be sex-limited as in 5-alpha reductase deficiency and persistent Müllerian duct syndrome.
Autosomal dominant disorders
Syndromes such as Frasier syndrome, Denys-Drash syndrome, and campomelic dysplasia have an autosomal dominant pattern of inheritance. In majority of cases, the parents are normal, and the disorder occurs due to a de novo mutation in the proband; therefore, the risk of recurrence in subsequent offspring of the parents is not significantly elevated. However, in some cases, there may be gonadal mosaicism in either parent leading to a small risk of recurrence, empirically given as ~1%.
X-linked disorders
Androgen insensitivity syndrome caused by a hemizygous variant in the AR gene has an X-linked recessive pattern of inheritance. If the mother is a heterozygous carrier of the variant, the risk of recurrence in subsequent male offspring is 50%. In cases where the mother is not a carrier, the empiric risk of recurrence due to gonadal mosaicism is around 1%.
CONCLUSION
Thorough clinical, genetic and endocrine evaluation are essential in every patient with a suspected DSD, to ensure appropriate management, prognostication, and genetic counseling.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The author confirms that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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