21α- Hydroxylase (cYP21) Deficiency
Congenital adrenal hyperplasia due to 21- hydroxylase deficiency is the commonest cause of 46XX DSD, accounting for up to 95% of all cases. Consensus guidelines exist for the management of this condition in infancy as well as in the older child. The newborn girl with this condition can be virilized to a varying extent, as illustrated by the Prader classification. High serum concentration of 17OH- progesterone (>300 nmol/ L) after the first 48 hours of birth and high androstenedione and testosterone in the early neo natal period are the biochemical hallmarks of this condition. More than 75% of these infants will also be salt losers because of a deficiency of mineralocorticoid synthesis and the affected child will present with a salt losing crisis in the second or third week of life.
3β- Hydroxysteroid Dehydrogenase (HSD3B2) Deficiency
3β- hydroxysteroid dehydrogenase type 2 catalyses the conversion of Δ5 steroids to Δ4 steroids and a deficiency of this enzyme results in adrenal insufficiency as well as accumulation of pregnenolone, dehydroepiandrosterone (DHEA), and androstenediol. In peripheral tissues, as well as the placenta, the accumulating steroids, and particularly DHEA, can be converted to more potent androgens, such as testosterone, by the Type 1 isoenzyme. Most girls with this condition present with relatively mild signs of virilization such as clitoromegaly, associated with adrenal deficiency.
P450 oxidoreductase (POR) Deficiency
Defects in P450 oxidoreductase can cause combined deficiencies of 21α- hydroxylase, 17α- hydroxylase, and aromatase enzymes and this can be associated with abnormal genital development in both girls and boys. Children with this condition usually have cortisol deficiency, but have normal mineralocorticoid function.
11β- Hydroxylase (CYP11B1) Deficiency
This is the second commonest cause of virilizing congenital adrenal hyperplasia accounting for approximately 5% of all cases. Apart from a DSD, this condition may also be associated with hypertension and hypokalaemia, but these abnormalities are not universally present, particularly, not in infancy. These abnormalities are due to the accumulation of 11- deoxycorticosterone which is a weak min eralocorticoid. They may be associated with a low renin. Children with this condition usually have cortisol deficiency.
Familial Glucocorticoid Resistance
This is a rare condition, usually due to a heterozygous mutation in the glucocorticoid receptor α gene. The partial end- organ insensitivity leads to high ACTH, cortisol, mineralocorticoids, and androgens. One case of a girl with a homozygous mutation in this gene and a coexisting heterozygous mutation in CYP21 has been described with marked virilization at birth.
P450 Aromatase Deficiency
Aromatase deficiency is inherited as a rare autosomal recessive condition caused by CYP19A1 gene mutation. There is often a history of maternal virilization after the second trimester of pregnancy coupled with elevated maternal androgen levels which resolve after the pregnancy. Urine from these mothers has elevated levels of 16α- hydroxyandrostenedione (16OH- D4A) and its metabolites. In infancy and subsequently during puberty, these girls have high serum androgens and low oestrogen concentrations as affected individuals cannot synthesize endogenous oestrogens. Girls show no signs of feminization and progressively virilize. Inadequate oestrogen supplementation may be associated with osteoporosis and a failure of timely epiphyseal fusion. Molecular testing of the CY19A1 gene is available.
Maternal Androgen Excess
Any maternal source of elevated androgens can induce virilization of the female fetus. Ovarian tumours include luteoma of pregnancy, arrhenoblastoma, hilar- cell tumour, masculinizing ovarian stromal cell tumour, and Krukenberg tumour. Discrepancy between the marked virilization of the mother and the minimal androgen ef fect in female offspring can be explained by the placental aromatase activity, which converts androgens to oestrogens, or to the metabolism of androgen, which thus becomes less active. Apart from untreated maternal virilizing CAH, androgen- secreting adrenal tumour in the mother is rare. In both cases, investigation of abnormal androgen production by the mother must be performed immediately after delivery. Maternal ingestion of androgens, progestogens, or other drugs is another cause of fetal virilization. Exogenous steroids administered during the pregnancy may cause posterior fusion of the labia, clitoral enlargement, and even increased degrees of an drogenization. In the past, several oral progestational compounds, given because of threatened abortion, have been implicated, such as 19- nor testosterone. Other drugs, like danazol or stilbestrol that are used in pregnancy, have also been associated with abnormalities of the genitalia.
