SRY gene abnormalities express with a clinical picture of 46,XY sex reversal with female phenotype. If gonads are not palpated at birth, it is probable that the diagnosis will be made in the pubertal period in the context of primitive amenorrhea associated with pubertal delay. However, some patients may present partial pubertal development, often caused by an association with a secreting gonadoblastoma [14]. This picture of 46,XY sex reversal is associated with a SRY gene mutation in 20 % of the cases.

About 80 % of the cases of gonadal dysgenesis are not caused by a SRY gene abnormality. They may be secondary to abnormalities in the other genes that take part in testis determination, however, and they are autosomal or X-linked.

Some cases of gonadal dysgenesis have been linked to SF1 gene mutation. This gene is involved in the development of male gonads and the adrenal glands [15]. The phenotype is variable, from severe expression [16] with isolated clitoral hypertrophy to moderate expression with hypospadias or isolated micropenis [17]. Adrenal insufficiency may be associated but is not systematically observed [18].

In some patients, the gonadal dysgenesis is associated with renal dysfunction. In these cases, the diagnosis of Drash syndrome—defined as Wilms tumor associated with renal insufficiency—or Frasier syndrome—which is proteinuria secondary to focal glomerular sclerosis—may be made. Both syndromes are due to WT1 gene abnormalities that are nevertheless quite specific for each syndrome. In particular, heterozygous mutations in the open reading frame have been associated with Drash syndrome [19], while intron mutations leading to splicing abnormalities have been found in Frasier patients [20].

Sox9 gene abnormalities have been reported. Sox9 is a key gene in early male sex determination [15]. Several mutations have been identified in patients with severe skeletal malformations like campomelic dysplasia, associated in some cases with sex reversal and gonadal dysgenesis [21–23].

Homozygous or composite heterozygous mutations of the desert hedgehog (DHH) gene, which is involved in testis differentiation and perineal development, have been identified. The virilization defect is frequently severe, the phenotype is often female, and a neuropathy may be associated.

A linkage study recently identified an MAP3K1 mutation in two families with several cases of 46,XY DSD, thus indicating another player in male sex determination [24].

In addition, duplications in the short arm of the X chromosome [dosage sensitive sex reversal (DSS) locus, DAX1 gene] have been reported in several cases of gonadal dysgenesis. A DSS locus duplication was found in 46,XY DSD patients with female phenotype (46,XY complete dysgenesis). Both the DAX1 (DSS-AHC critical region on X chromosome, gene 1) and NR0B1 (nuclear receptor 0B1) genes have been identified in this locus. The NR0B1 gene belongs to the nuclear receptor family and, through its linkage with other transcription factors such as SF1, it has an “anti-testis” effect during the process of male sex determination, proportional to the gene dosage. Thus, the overexpression of the DAX gene, as in the case of duplication in a 46,XY patient, may contrast with normal testis differentiation, leading to gonadal dysgenesis [25].

Last, a chromobox homolog 2 (CBX2) gene mutation was recently identified in a newborn with complete female phenotype but a 46,XY karyotype, which had been determined in the prenatal period because of concerns about maternal age. This testis differentiation abnormality nevertheless differed from the previously presented cases of gonadal dysgenesis in that ovaries with primordial follicles were detected [26]. A mutation in the CBX2 gene, which is known for activating SF1 transcription, was identified in this patient. The CBX2 gene thus seems to actively repress ovarian development in 46,XY gonads.

This defect is associated with a variable but insufficient virilization of the 46,XY fetus, ranging from a female phenotype to minor forms of DSD, such as isolated micropenis or salt-wasting conditions. The biological and genetic investigations are the same as for 46,XX DSD.

The phenotype in cases of a 17-alpha-hydroxylase defect may also be extremely variable. In some individuals, the diagnosis is made only in the pubertal period because of pubertal delay or stagnation associated with gynecomastia. A DOC excess causes hypertension during puberty. The plasma levels of pregnenolone, progesterone, and corticosterone are elevated, which contrasts with the low values of T and D4 that are unresponsive to stimulation. The genetic abnormality concerns the CYP17 gene with recessive transmission.

This is a rare testicular block that causes a deficit in testicular T production. The phenotype is more frequently female at birth. The diagnosis is based on a striking elevation in plasma D4 contrasting with a low T level. The mutation involves the 17ß-HSD type 3 gene, which is expressed only in testis, and its transmission is recessive. Virilization occurs at puberty associated with gynecomastia.

A POR deficit may cause 46,XY DSD as well as 46,XX DSD [7]. The cytochrome P450 oxydoreductase protein enables the electron transport from NADPH to P450 cytochromes localized in microsomes. Several cytochromes take part in cholesterol biosynthesis, while three are involved in steroid biosynthesis: P450C17 (17a-hydroxylase/17,20 lyase), P450C21 (21-hydroxylase), and P450CYP19 (aromatase). Transmission of POR gene mutations is autosomal recessive, and the study of several of these mutations has provided greater insight into DSD in association with combined deficits in 21-OH and 17-OH in cases where molecular analysis of CYP21 and CYP17 was normal. In addition to DSD, several patients present craniofacial malformations, suggestive of Antley-Bixler syndrome. The great variability in the phenotype and endocrine findings makes this diagnosis very difficult. This may be due in part to the varying degrees of the enzymatic defects and to the differences in the ability of each mutation to alter enzyme function [27].

This is a rare form of 46,XY DSD, first identified in a patient with female phenotype associated with the 46,XY karyotype. She presented primary amenorrhea and no breast development at puberty, associated with low T at baseline and after hCG stimulation testing. The discrepancy between increased LH and normal FSH levels is generally evocative. This condition is determined by a homozygous or double heterozygous inactivating mutation of the LH receptor gene. Since the identification of these genetic abnormalities, the phenotypic expression has expanded to include conditions that range from ambiguous genitalia to partial forms such as hypospadias or isolated micropenis [28].