Table 4.

Disorders to Consider in the Differential Diagnosis of Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

Differential
Category		EtiologyPhenotype
Sex
chromosome
aneuploidies 		47,XXY (& variants:
48,XXXY; 49,XXXXY; 46XY/47,XXY mosaicism)
  • Klinefelter syndrome (males w/hypogonadism, small testes, gynecomastia)
  • Unlike 46,XX testicular DSD, Klinefelter syndrome is often characterized by normal or tall stature, speech delay, learning disorders, & behavioral issues.
46,XX/46,XYMay present w/external genitalia ranging from typical male to ambiguous to typical female
45,X/46,XYAffected persons often present as male & may have short stature; may be clinically indistinguishable from 46,XX testicular DSD.
Syndromic
forms of
46,XX
testicular
DSD 		RSPO1 Biallelic pathogenic variants are assoc w/palmoplantar hyperkeratosis with squamous cell carcinoma of skin & 46,XX testicular DSD. 1
Yp translocation assoc w/partial or complete Xp monosomyRare 46,XX males in whom the translocation of Y material to the X chromosome has resulted in loss of X material may present w/syndromic form associating an XX karyotype & male or ambiguous genitalia w/characteristics of partial monosomy Xp, as in microphthalmia with linear skin defects syndrome (MIDAS complex), an X-linked disorder generally lethal in XY persons.
Balanced translocation involving SOX9 246,XX testicular DSD w/dysmorphic facial features
Deletion of multiple genes around SOX3 or Mb-size duplications incl SOX3 346,XX testicular DSD & DD (w/o ambiguous genitalia)
NR2F2 Frameshift variant in or deletion of NR2F can cause testicular or ovotesticular DSD assoc w/cardiac malformations. 4
Prenatal
exposure of
46,XX fetuses
to androgens 		CYP21A2
  • Biallelic pathogenic variants are assoc w/21-hydroxylase deficiency (most common cause of congenital adrenal hyperplasia); excessive adrenal androgen biosynthesis results in virilization in all persons & salt wasting in some.
  • Virilized females may have an enlarged clitorophallic structure & urogenital sinus; uterus & ovaries are normal.
Externally administered androgens (e.g., danazol) or androgens endogenously produced by the motherVirilization resulting in an infant w/ambiguous genitalia that may look similar to those of a male w/46,XX testicular DSD & ambiguous genitalia

DD = developmental delay; Mb = megabase

1.

See OMIM 610644.

2.

46,XX,t(12;17)(q14.3;q24.3) [Refai et al 2010] and 46,XX,t(11;17)(p13;q24.3) [Vetro et al 2015]

3.
4.

See OMIM 618901.

From: Nonsyndromic 46,XX Testicular Disorders/Differences of Sex Development

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