Clinical Description
Approximately 85% of individuals with a nonsyndromic 46,XX testicular disorder of sex development (46,XX testicular DSD) present after puberty with normal pubic hair and normal penile size, but small testes, gynecomastia, and sterility resulting from azoospermia [Zenteno-Ruiz et al 2001]; up to 90% of these individuals are SRY positive [McElreavey et al 1993]. The small testes are usually soft but may become firmer with age. Among these individuals, a minority have cryptorchidism (undescended testes) and/or anterior hypospadias (atypical urethral opening) [Boucekkine et al 1994]. Gender role and gender identity are reported as male for the common, unambiguous presentation, but systematic psychosexual assessment has not been performed on a significant number of individuals with 46,XX testicular DSD.
Approximately 15% of individuals with a nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia, typically penoscrotal hypospadias with or without chordee [Zenteno-Ruiz et al 2001]; only a minority of these individuals are SRY positive [Fechner et al 1993, McElreavey et al 1993, Boucekkine et al 1994].
Nonsyndromic 46,XX testicular DSD is not associated with learning disorders or behavioral issues.
The natural history of individuals with nonsyndromic 46,XX testicular DSD, if untreated, is similar to the typical consequences of testosterone deficiency:
Low libido and possible erectile dysfunction
Decrease in secondary sexual characteristics, such as sparse body hair, infrequent need to shave, and reduced muscle mass
Increase in fat mass with lower muscle strength
Increased risk of osteopenia
Increased risk of depression
SRY-positive nonsyndromic 46,XX testicular DSD. Individuals with SRY-positive 46,XX testicular DSD typically present after puberty with the following:
Shorter-than-average stature (mean height: 168.2 cm, compared to normal mean height: 173.5 cm) [
de la Chapelle 1972]
Gynecomastia
Small testes
Azoospermia
Individuals with SRY-positive 46,XX testicular DSD rarely present with atypical genitalia and are less likely than individuals with SRY-negative 46,XX testicular DSD to have gynecomastia [Ferguson-Smith et al 1990, Boucekkine et al 1994, Ergun-Longmire et al 2005].
SRY-negative nonsyndromic 46,XX testicular DSD. Individuals with SRY-negative 46,XX testicular DSD tend to present with ambiguous genitalia at birth, such as penoscrotal hypospadias and cryptorchidism, and, if untreated, almost always develop gynecomastia around the time of puberty.
SOX9-related nonsyndromic 46,XX testicular DSD. Of the limited number of individuals with confirmed SOX9-related 46,XX testicular DSD reported to date, none presented in the newborn period with ambiguous genitalia, one was ascertained at age four years with small testes as the sole finding, and three presented as adults with infertility and azoospermia.
A primary presentation of delayed puberty has not been reported.
As gonadal biopsy is not routinely performed, it is unclear what percentage of individuals with copy number variants in and around SOX9 have testicular DSD vs ovotesticular DSD, an allelic disorder.
SOX3-related nonsyndromic 46,XX testicular DSD. Shorter-than-average stature, small testes with azoospermia, and low testosterone are seen in affected individuals.
Only one of five affected individuals presented at birth with atypical male genitalia. One affected individual was diagnosed in adulthood because of infertility. In the other three individuals, SOX3-related 46,XX testicular DSD without genital ambiguity was discovered during consultation for developmental delay or gender dysphoria (see Differential Diagnosis for discussion of syndromic forms of DSD).
Genotype-Phenotype Correlations
In nonsyndromic 46,XX testicular DSD, the presence of SRY is often associated with the presence of normal male external genitalia, whereas the absence of SRY is more often associated with ambiguous genitalia [Grigorescu-Sido et al 2005]. However, genotype-phenotype correlation is not entirely reliable, because a small number of individuals with SRY-negative nonsyndromic 46,XX testicular DSD have typical male external genitalia [Vilain et al 1994, Zenteno et al 1997, Kolon et al 1998, Vernole et al 2000, Abusheikha et al 2001]. This number may increase as larger cohorts of adults undergoing evaluation for fertility problems are tested. A recent study found three individuals with a 46,XX karyotype among 555 infertile adult Taiwainese males; two of the three individuals were SRY positive [Chiang et al 2013].
Due to the small number of individuals reported with SOX9-related 46,XX testicular DSD and SOX3-related 46,XX testicular DSD, genotype-phenotype correlations are not yet available.