Intersex Disorders
In spite of many advances in the field of endocrinology, molecular biology and genetics, intersex disorder remains the most challenging clinical situation for the caring physician. It is also very traumatic for the parents and the family of the affected baby.
Children with this disorder often present very late particularly in countries like India. Late presentation adds to the complexity of the medical management.
Special training of the caring staff and extreme sensitivity of the whole team is necessary for a successful outcome.
Definition:
Intersex disorders are suspected when phallus is too small to call it a penis or too large to call a clitoris, or an infant with a short mid-line cleft separating two folds that could either be two sides of scrotum or unusual looking labia. Such an infant may or may not have palpable gonad(s).
Etiology:
Various disorders at several levels of sexual differentiation from genetic defects to end organ resistance can cause this complex clinical condition.
Abnormality in the following processes are known to cause intersex disorders:
Gonadal differentiation, biosynthetic defects of testosterone and MIS, the response of the target tissues to Testosterone and MIS and adrenosteroid biosynthesis,
Classification:
Earlier the classification was female pseudohermaphroditism, male pseudohermaphroditism, mixed gonadal dysgenesis and true hermaphroditism. Since these terminologies are unclear and unacceptable to many, classification is changed.
Classification:
- Intersex disorders associated with ambiguous genitalia:
- Chromosomes 46XX
- CAH,
- Maternal androgens,
- Teratogens,
- Placental aromatase deficiency.
- Chromosomes 46XY
- Inadequate testosterone
- Testosterone biosynthetic defects,
- Leydig cell hypoplasia
- Androgen resistance
- PAIS,
- alpha reductase deficiency.
- Gonadal dysgenesis
- Partial (mixed) gonadal dysgenesis,
- True hermaphrodite
- Syndromes
- Intersex disorders associated with normal male or female external genitalia:
- Chromosomes 46XX, Male phenotype
1) XX male (Y-X translocation), 2) Virilizing CAH (No palpable gonads)
- Chromosomes 46XY, female phenotype
- CAIS
- Complete gonadal dysgenesis
- Complete block in testosterone biosynthesis
- Female phenotype with streak gonads
- Turner
- Familial 46XX gonadal dysgenesis
- Complete gonadal dysgenesis
Female phenotype with absent Mullerian structures
- Vaginal agenesis
- R K H syndrome
Male phenotype with persistent Mullerian structures
- MIS gene mutation
- MIS receptor gene mutation
Clinical features:
Clinical clues that help in making the diagnosis:
- Familial genital abnormality – Genetic condition
- Association of extra genital abnormalities – Syndromes
- Perineal hypospadias – A defect in the androgen secretion or action
- Both gonads absent and abnormal phallus – virilized female often CAH
- Genital abnormality in a sick newborn who is also hyperpigmented – CAH in crisis
- Genital asymmetry – mixed gonadal dysgenesis or true hermaphrodite
Investigations:
- Karyotype
- LH, FSH
- Testosterone and dihydrotestosterone
- HCG stimulation test
- Additional tests:
- ACTH
- 17 hydroxyprogesterone
- Cortisol
- Androstenedione
- Dheas
- Aldosterone
- 11 deoxycortisol
- Electrolytes
- Imaging: Pelvic ultrasound / MRI of the abdomen & pelvis
- Genitography and genitoscopy
- Laproscopy, laparotomy and gonadal biopsy.
Management
The diagnosis and gender assignment is needed promptly but can be delayed for weeks until all the tests are available. Psychological support to the family is needed at this difficult time. Gender assignment is based on the potential for future sexual and reproductive function, nature of anatomic abnormalities and the feasibility of surgical correction. Virilized newborns with 46XX karyotype should be raised as females. Individuals with 46XY with CAIS are also raised as females. In individuals with PAIS with less than 2.0 cm phallic length, response to exogenous androgens is considered favorable for male sex assignment if phallus enlarges to greater than 2.5 cms.
Risk of gonadal malignancy:
Presence of Y chromosome in a child with intersex increases the risk gonadoblastoma and dysgerminoma. Therefore if an XY child with ambiguity is raised as a female, the gonads should be removed. If raised as a male, the gonads should be brought down to the scrotum and examined at a regular interval.
Fertility:
Females with CAH can get naturally fertile provided monitored treatment is given through out life. Patients with PAIS, gonadal dysgenesis or 17ß HSD are all infertile. It is possible for XY individuals with a uterus to become pregnant through In Vitro Fertilization. In true hermaphrodites few pregnancies are reported but paternity is rare.
Conclusion:
A child with intersex disorder needs an urgent referral to a place where expert opinion is readily available. A prompt diagnosis and management plan needs to be individualized in each case. Effective management can be offered to all children even if they present late although the outcome will always be more favorable if they present early.
