Dr. Vaman Khadilkar
MD, DNB, MRCP (UK), DCH (London)
Pediatric & Adolescent Endocrinologist,
Jehangir & Deenanath Mangeshkar hospital, Pune & Bombay hospital, Mumbai
Introduction:
In spite of many advances in the field of endocrinology, molecular biology and genetics, intersex disorders remain 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 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 has a short midline 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. Following conditions are known to cause intersex:
- Abnormality in gonadal differentiation,
- Biosynthetic defects of testosterone and MIS
- Adrenal steroid biosynthesis defects.
Classification: In the past Intersex disorders were classified as female pseudohermaphroditism, male pseudohermaphroditism, mixed gonadal dysgenesis and true hermaphroditism. Since these terminologies are unclear and unacceptable to many, classification is now changed.
Newer Classification:
Intersex disorders associated with ambiguous genitalia:
- Congenital Adrenal Hyperplasia
- Maternal androgens
- Teratogens
- Placental aromatase deficiency
- Chromosomes 46XY
- Inadequate testosterone
- Testosterone biosynthetic defects
- Leydig cell hypoplasia
- Androgen resistance
- Partial androgen insensitivity syndrome (PAIS)
- 5 alpha reductase deficiency
- Gonadal dysgenesis
- Partial (mixed) gonadal dysgenesis
- True hermaphrodite
- Syndromes
Intersex disorders associated with normal male or female external genitalia:
- Chromosomes 46 XX, Male phenotype
- XX male (Y-X translocation)
- Virilizing CAH (No palpable gonads)
- Chromosomes 46 XY, female phenotype
- Complete Androgen Insensitivity Syndrome (CAIS)
- Complete gonadal dysgenesis
- Total block in testosterone biosynthesis
- Female phenotype with streak gonads
- Turner’s syndrome
- Familial 46 XX gonadal dysgenesis
- Complete gonadal dysgenesis
- Female phenotype with absent Mullerian structures
- Vaginal agenesis
- Rokitansky Kustner Hauser syndrome
- Male phenotype with persistent Mullerian structures
- MIS gene mutation
- MIS receptor gene mutation
Clinical features: Clinical clues that help in making the diagnosis:
- Both gonads absent and abnormal phallus - virilized female often CAH
- Perineal hypospadias - A defect in the androgen secretion or action
- Familial genital abnormality - Genetic condition
- Association of extragenital abnormalities - Syndromes
- Genital abnormality in a sick newborn who is also hyperpigmented - CAH in crisis
- Genital asymmetry - Mixed gonadal dysgenesis or true hermaphrodite
Approach to diagnosis:
Investigations:
- Karyotype
- LH, FSH
- Testosterone and dihydrotestosterone HCG stimulation test (Measure Testosterone and DHT before and after)
- HCG stimulation test (Measure Testosterone and DHT before and after)
- Adrenal tests:
- ACTH
- 17 hydroxyprogesterone
- Cortisol
- Androstenedione
- DHEAS
- Aldosterone
- 11 deoxycortisol
- Electrolytes, glucose
- Imaging
- Pelvic ultrasound
- MRI of the abdomen & pelvis
- Genitography & genitoscopy
- Laproscopy, laparotomy & gonadal biopsy
Important Management points:
Gender assignment: The diagnosis and gender assignment is needed promptly but may have to 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 46 XX 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 cms 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 of 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 throughout 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.
Conclusions: A child with intersex disorder needs an urgent referral to a place where expert opinion and laboratory support 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.
