Disorders of Sexual Differentiation

Definition of Terms

1. Chromosomal Sex:

   The sex determined by the presence of specific sex chromosomes in an individual. Typically, XX corresponds to female chromosomal sex and XY corresponds to male chromosomal sex.

2. Gonadal Sex:

   The sex determined by the presence of specific gonads (ovaries or testes). It refers to the type of gonads an individual has, which produce sex hormones (estrogens or androgens) and gametes (eggs or sperm).

3. Phenotypic Sex:

   The observable physical characteristics of an individual that are determined by the interaction between chromosomal sex, gonadal sex, and hormonal influences. This includes secondary sexual characteristics such as breast development, facial hair, and genital morphology.

4. Gender Identity:

   An individual's personal sense of their own gender, which may or may not align with their chromosomal or phenotypic sex. It is a deeply felt experience of being male, female, a blend of both, or neither.

5. Gender Role:

   The social and cultural expectations and behaviors associated with being male or female in a given society. This includes roles, activities, and responsibilities that society considers appropriate for individuals based on their gender.

Revised nomenclature
Previous	Current
Intersex	Disorders of sex development (DSD)
Male pseudohermaphrodite Undervirilisation of an XY male Undermasculinisation of an XY male	46,XY DSD
Female pseudohermaphrodite Overvirilisation of an XX female Masculinisation of an XX female	46,XX DSD
True hermaphrodite	Ovotesticular DSD
XX male or XX sex reversal	46,XX testicular DSD
XY sex reversal	46,XY complete gonadal dysgenesis

Causes of ambiguous genitalia in infants with 46XX karyotype
Problem	Cause	Specific examples
Excessive androgens of foetal origin	Congenital adrenal hyperplasia Testis or ovotestis present	21-hydroxylase deficiency 11β-hydroxylase deficiency 3β-hydroxyl steroid dehydrogenase deficiency Partial gonadal dysgenesis
Androgens crossing the placenta	Maternal ingestion of virilising drug Virilising disease in mother	Danazol, progestogens Adrenal tumour or hyperplasia Ovarian tumour
Non-androgenic	Isolated cliteromegaly e.g. neurofibromatosis

Causes of ambiguous genitalia in infants with 46XY karyotype
Problem	Cause	Specific examples
Insufficient androgen	Gonadal dysgenesis Block in testosterone synthesis Primary Leydig cell hypoplasia	SRY gene mutation 17-ketosteroid reductase deficiency 3β-hydroxysteroid dehydrogenase deficiency Unresponsiveness to LH/hCG
Impaired response to androgen	Abnormal androgen receptor Deficient conversion of testosterone to DHT	Partial androgen insensitivity syndrome 5α-reductase deficiency

Clinical features & diagnosis of ambiguous differential s genitalia
Palpable gonad(s)	-	+	+	+
Uterus present	+	+	-	-
↑ pigmentation	+	-	-	-/+
Sick baby	+/-	-	-	-/+
Dysmorphic appearance	-	+/-	-	-
Clinical diagnosis	21-OH deficiency	Gonadal dysgenesis with Y chromosome	Partial androgen insensitivity	Block in testosterone synthesis

1. Electrolytes:

   Assess for imbalances such as sodium, potassium, and chloride. Imbalances, especially hyponatremia and hyperkalemia, can suggest a salt-wasting form of CAH.

2. 17-Hydroxyprogesterone (17-OHP) & Cortisol:
   • 17-OHP: Elevated levels can indicate 21-hydroxylase deficiency in CAH.
   • Cortisol: Low levels can confirm cortisol deficiency.
3. Pelvic Ultrasound:

   Evaluate the internal genitalia to determine the presence and morphology of the uterus, ovaries, and testes. This helps in differentiating between male and female internal genital structures.

4. Karyotype:

   Perform chromosomal analysis to determine the chromosomal sex (XX or XY) and confirm the genetic sex of the child.

5. Hormone Levels:
   • Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH): Assess gonadotropin levels to evaluate pituitary function and gonadal response.
   • Dehydroepiandrosterone sulfate (DHEAS): Elevated levels can indicate adrenal hyperplasia.
   • Androstenedione, Testosterone, and Dihydrotestosterone (DHT): Measure to evaluate androgen levels and assess the degree of virilization.
6. Additional Investigations:
   • Urinary Steroid Metabolites: Analyzing these can provide insight into the steroid biosynthesis and metabolism.
   • Luteinizing Hormone-Releasing Hormone (LHRH): May be assessed to evaluate hypothalamic function.
   • Human Chorionic Gonadotropin (HCG): Can help in identifying testicular tissue in males and assess hormone production.
   • Renin and Aldosterone: Evaluating these can help in diagnosing mineralocorticoid deficiencies and assessing adrenal function.

1. Multidisciplinary Team Involvement:
   • Parents: Integral in decision-making and support.
   • Pediatrician: Oversees general health and development.
   • Endocrinologist: Manages hormonal imbalances and disorders.
   • Pediatric Surgeon: Performs necessary surgical interventions.
   • Geneticist: Provides genetic counseling and analysis.
   • Clergy: May offer spiritual support.
   • Psychologist/Counselors: Supports emotional and psychological well-being.
   • Lawyer: Assists with legal issues, particularly in complex cases.

Management Steps:

1. Investigation & Diagnosis:
   • Conduct thorough investigations to identify the underlying cause of ambiguous genitalia.
   • Diagnosis involves a combination of clinical, hormonal, genetic, and imaging studies.
2. Coordinating with Specialists:
   • Work with the multidisciplinary team to discuss findings and formulate a management plan.
   • Gender Assignment: Determine the most appropriate gender for rearing based on feasibility of genital reconstruction and potential fertility, rather than solely on karyotype or gonads.
3. Counseling:
   • Provide support to the family and child regarding diagnosis, treatment options, and potential outcomes.
   • Address emotional, psychological, and social aspects of gender assignment and future implications.
4. Medical Therapy:
   • Initiate appropriate hormonal treatments to address endocrine imbalances.
   • Implement therapies based on the specific diagnosis and individual needs of the child.
5. Long-Term Follow-Up:
   • Regularly monitor the child’s growth, development, and psychological well-being.
   • Continue to assess and address any ongoing medical, developmental, or social issues.

Major Goals:

• Identification of Life-Threatening Disorders: Ensure that any potentially life-threatening conditions are identified and managed promptly.
• Determination of Correct Sex of Rearing: Based on the feasibility of genital reconstruction and potential fertility, rather than solely on karyotype or gonads, to provide the best long-term outcomes for the child.

1. Replace Deficient Hormones:

   Administer appropriate hormone replacement therapy to correct hormonal deficiencies and restore normal physiological functions. This may include glucocorticoids, mineralocorticoids, or sex hormones depending on the specific diagnosis.

2. Surgical Correction:

   Perform surgical interventions to correct ambiguous genitalia and achieve a more typical genital appearance. Surgical options should be considered carefully, taking into account the child’s age, the feasibility of reconstruction, and the potential for future fertility.

3. Removal of Dysgenetic Gonads:

   In cases where gonads are non-functional or dysgenetic (e.g., streak gonads or dysgenetic testicular tissue), surgical removal may be necessary to prevent potential malignancies and avoid complications associated with non-functional gonads.

4. Psychological Support for the Whole Family:

   Provide psychological and emotional support to the child and family throughout the diagnosis, treatment, and adjustment processes. Counseling services should address the psychological impact of ambiguous genitalia, gender assignment, and ongoing treatment, and offer support for coping with the social and emotional challenges faced by the family.