Defects anywhere along the pathway of androgen synthesis and target organ action can result in an XY DSD.
Cholesterol Synthesis Defects
A deficiency of 7- dehydrocholesterol reductase (DHCR7) results in a failure of cholesterol synthesis and results in the Smith– Lemli– Opitz syndrome. This is associated with a wide range of clinical features including microcephaly, cardiac defects, micrognathia, cleft palate, polydactyly, and syndactyly. In childhood, these children may display intellectual disability and growth failure. The genitalia in the affected XY infant may range from hypospadias to completely normal female external genitalia with no Müllerian ducts. The condition is diagnosed by low levels of cholesterol and elevated levels of its precursor, 7- dehydrocholesterol, as well as an androgen deficiency and a normal AMH. Adrenal insufficiency may occur in some cases and needs evaluation. Mutational ana lysis of the DHCR7 gene will provide further confirmation of the diagnosis.
Leydig cell Hypoplasia
A defect of the luteinizing hormone- choriogonadotropin receptor (LHCGR) gene leads to impaired sensitivity to hCG and LH and Leydig cell agenesis or hypoplasia. The genitalia in the affected XY infant may range from isolated hypospadias or micropenis to completely normal female external genitalia with no Müllerian ducts. The biochemical picture may include high basal and luteinizing hormone- releasing hormone (LHRH)- stimulated luteinizing hormone (LH) and follicle- stimulating (FSH) levels. There is a poor response to hCG stimulation and the AMH levels should be normal. Histology of the testes in the prepubertal child will show a marked lack of Leydig cells. Mutational analysis of the LH/ hCG receptor gene provides further confirmation of the diagnosis.
Congenital Lipoid Adrenal Hyperplasia
Defects in the steroidogenic acute regulatory (StAR) protein lead to deranged intracellular transport of cholesterol and abnormalities of steroid biosynthesis. Affected XY infants have severe adrenal failure and the external genitalia are unambiguously female with no Müllerian structures. The testes may be palpable in the labioscrotal folds but are usually undescended. CT or MRI imaging of the adrenal glands, as well as histology, may reveal lipid accumulation. This condition is commoner in Japan and Korea. A non- classical form of this condition also exists and is associated with progressive adrenal insufficiency in early child hood but without any overt abnormalities of androgen synthesis. Mutational analysis of the StAR gene will provide further confirmation of the diagnosis.
P450 Side chain cleavage Deficiency
Defects in the P450scc enzyme result in a failure of conversion of cholesterol to pregnenolone which is the first common step in steroid biosynthesis. Affected XY infants have a phenotype which is very similar to congenital lipoid adrenal hyperplasia due to defect of StAR protein. Mutational analysis of the P450scc gene (also called CYP11A1) will provide further confirmation of the diagnosis.
3β- Hydroxysteroid Dehydrogenase (3β- HSD) Type 2 Deficiency
Defects in 3β- HSD Type 2 results in a failure to convert Δ5- steroids to Δ4- steroids. The genitalia in the affected XY infant may range from isolated hypospadias or micropenis to more severe undermasculinization but not completely normal female external genitalia. There are no Müllerian ducts. Besides a poor androgen response to hCG stimulation, affected infants will have adrenal deficiency which may not necessarily include salt wasting. A urine steroid profile that shows high concentrations of Δ5- steroids (e.g. 17OH- pregnenolone, pregnenolone, dehydroepiandrosterone) and low concentrations of Δ4- steroids (e.g. progesterone and cortisol) is helpful. However, there is a need for careful analysis and interpretation of the steroid profile as extra- adrenal/ gonadal 3β- HSD type 1 may raise the levels of some Δ4- steroids such as androstenedione and 17OH- progesterone. In addition, raised 17- OHP can lead to an erroneous diagnosis of 21 hydroxylase deficiency. Mutational ana lysis of the 3β- HSD Type 2 gene (also called HSD3B2) will provide confirmation of the diagnosis.
17α- Hydroxylase/ 17,20- Lyase Deficiency
Defects of the P450c17 enzyme can lead to a variable extent of a combined deficiency of 17α- Hydroxylase and 17,20- Lyase activity. In the affected XY infant, this will be associated with a variable degree of undermasculinization ranging from mild abnormalities of the genitalia to unambiguously female external genitalia. These account for around 1% of cases of 46,XY DSD. Besides a poor androgen response to hCG stimulation, affected infants will have a poor cortisol response to adrenal stimulation but may not display adrenal insufficiency as they have highly raised deoxycorticosterone levels which may lead to a state of low renin hypertension and hypokalaemic alkalosis in the older child. Mutational analysis of the P450c17 gene (also called CYP17) will provide confirmation of the diagnosis.
P450 oxidoreductase Deficiency
The P450 oxidoreductase enzyme is necessary for electron transfer from NADP to many P450 enzymes and its deficiency can affect the activity of a number of P450 enzymes. Infants with XY DSD and an abnormality of this enzyme tend to present with a clinical picture consistent with combined deficiency of 21α- hydroxylase deficiency and 17,20- lyase deficiency. The genitalia in the affected XY infant may range from isolated hypospadias or micropenis to more severe undermasculinization but not completely normal female external genitalia. There are no Müllerian ducts. Besides a poor testosterone response to hCG stimulation, affected infants will have adrenal deficiency which is usually restricted to glucocorticoid deficiency. The deficiency of this enzyme may be associated with a condition called Antley– Bixler syndrome which is a skeletal dysplasia classically characterized by radiohumeral stenosis and craniosynostosis. This syndrome is not universally associated with abnormalities of the P450 oxidoreductase enzyme. Mutational analysis of the P450 oxidoreductase gene (also called POR) may provide confirmation of the diagnosis.
17β- Hydroxysteroid Dehydrogenase (17β- HSD) Type 3 Deficiency
17β- HSD has 6 isoenzymes which convert androstenedione, DHEA and estrone to testosterone. Deficiency of 17β- HSD Type 3 is associated with XY DSD and affected infants often present with fe male external genitalia or sometimes ambiguous genitalia. However, these children can undergo spontaneous virilization during puberty with a rise in testosterone levels, possibly due to increased activity of the other isoenzymes. Thus, early accurate diagnosis of this condition is important as the affected infant may need sex reassignment if initially raised as a girl (see section, ‘Sex Assignment in the Affected Newborn’). These infants shall have a poor testosterone response to hCG but may have a relatively high level of serum androstenedione such that the testosterone:androstenedione ratio may be less than 0.8. However, this is not an invariable finding in this condition; furthermore, a low ratio may also be found in poorly functioning testes. Mutational analysis of the 17β- HSD type 3 gene (also called HSD17B3) will provide confirmation of the diagnosis.
Steroid 5α- Reductase (5α- RD) Type 2 Deficiency
5α- RD exists as two isoenzymes. Type 1 is expressed in skin and type 2 in the genitalia. In XY DSD infants may present with a vari able phenotype ranging from micropenis or hypospadias to female external genitalia. This phenotype is due to reduced activity of 5α- RD type 2 and a failure to convert testosterone to dihydrotestosterone. The classical biochemical profile includes a high testosterone: dihydrotestosterone ratio following hCG stimulation (normal ratio is < 25:1) although many affected cases have a lower ratio. An additional diagnostic feature is a urinary steroid profile which shows a decreased ratio for 5α:5α- reduced C21 and C19 steroids. It may not be possible to detect this abnormality in the urine until late infancy. Like 17β- HSD type 3 deficiency, these children can undergo spontaneous virilization during puberty with a rise in testosterone levels, possibly due to increased activity of the Type 1 isoenzymes. Thus, early accurate diagnosis of this condition is important as the affected infant may need sex reassignment if initially raised as a girl (see section, ‘Sex Assignment in the Affected Newborn’).
