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Conditions

Differences in sex development

Differences in sex development are a group of rare conditions where chromosomal, gonadal or anatomic sex is atypical.

Overview

Differences in sex development are a group of rare conditions where chromosomal, gonadal or anatomic sex is atypical.

Clinical features

Presenting features will differ depending on the underlying aneuploidy, hormonal disruption, or both. Ambiguous genitalia may or may not be a feature of DSD. Below are some clinical features that may alert you to an underlying DSD.

  • Neonatal period:
    • discordance between prenatal karyotype or ultrasound and appearance of genitalia in the newborn;
    • micropenis or enlarged clitoris;
    • labioscrotal folds: bifid scrotum or labial fusion;
    • impalpable or undescended gonads in males;
    • displacement of the urethra: hypospadias or chordee;
    • pigmented scrotum; and
    • failure to thrive, hyponatraemia and dehydration.
  • Childhood:
    • precocious puberty;
    • short stature; and
    • tall stature.
  • Adolescence:
    • oligo- or amenorrhoea;
    • hirsutism;
    • acne; and
    • gynaecomastia.
  • Adulthood
    • hirsutism;
    • oligomenorrhoea; and
    • infertility.

Genomics

There are a number of genetic and chromosomal causes for DSD that include (though are not limited to) the following:

46,XY DSD

  • Conditions associated with androgen synthesis/action, including:
    • 5 alpha reductase deficiency: SRD5A2 gene.
      • May present as perineoscrotal hypospadias or male pseudohermaphroditism (46,XY with female appearance of external genitalia).
    • Complete androgen insensitivity syndrome (CAIS): AR gene.
      • Pathogenic variants in AR prevent binding of androgens.
      • 46,XY individuals develop female external genitalia and blindending vagina, and often present with bilateral inguinal hernias (typically testes) in infancy/early life, or with primary amenorrhoea.
    • Partial androgen insensitivity syndrome (PAIS): AR gene.
      • Impaired androgen binding and signalling lead to range of ambiguous genitalia.
    • Smith-Lemli-Opitz syndrome (SLO): DHCR7 gene.
      • Autosomal recessive disorder resulting from deficiency of 7-dehydrocholesterol reductase.
      • 46,XY individuals may have genital hypoplasia, hypospadias and undescended testes.
      • This condition also presents in individuals with 46,XX. Individuals with 46,XY or 46,XX can present with microcephaly, congenital heart disease, Y-shaped 2-3 toe syndactyly, cleft palate and developmental delay.
    • 17 beta-hydroxysteroid dehydrogenase deficiency: HSD gene, or 9q22 deletion.
      • Male form of DSD with gynecomastia due to impaired conversion of androstenedione to testosterone.
  • Conditions associated with testicular development (complete or partial gonadal dysgenesis), including:
    • Campomelic dysplasia: SOX9 gene.
      • Can present with ambiguous genitalia or complete sex reversal.
      • Presents with femoral and tibial bowing, hip dislocation, narrow chest, short hands, macrocephalia, low-set ears and cleft palate.
    • Denys-Drash syndrome (DDS) and Frasier syndrome: WT1 gene.
      • Autosomal dominant conditions associated with ambiguous genitalia (some males present with pseudohermaphroditism in DDS), renal impairment and nephropathy, Wilms tumour (DDS) and gonadoblastoma (Frasier syndrome).
    • WAGR (Wilms tumour, aniridia, genitourinary anomalies and range of developmental delay) syndrome: contiguous gene deletion on chromosome 11, position 11p12, including PAX6 and WT1 genes.
    • Testes determining genes: DMR1, DMR2 or 9p24.3 deletion.
      • Range of gonadal dysgenesis and XY sex reversal.
      • Microcephaly, developmental delay, short stature and bronchial or digestive malformations.
    • 46,XY sex reversal 1: SRY gene.
      • Pathogenic variants or deletions involving SRY (10%–20% of 46,XY females).
    • 46,XY sex reversal 2: NR0B1 or DAX1 genes, or duplication on chromosome Xp21.3-21.2.
      • A dosage-sensitive, X-linked male to female sex reversal.
    • 46,XY sex reversal 3: NR5A1 gene.

46,XX DSD

  • Conditions associated with fetal androgen excess, including:
    • Congenital adrenal hyperplasia (CAH): CYP21A2, TNXB, CYP11B1, CYP17A1, CYP11A1 genes.
      • Most common cause of ambiguous genitalia in neonates with 46,XX.
      • Autosomal recessive disorder arising from deficiency of enzymes required for cortisol synthesis.
      • In individuals with 46,XX, the classical form presents with ambiguous genitalia; the non-classical form may be asymptomatic or present with abnormal menses, hirsutism and infertility.
      • This condition also presents in individuals with 46,XY with normal male genital development but with salt loss (classical form) or early pubarche (non-classical form).
  • Conditions associated with ovarian development, including:
    • Palmoplantar hyperkeratosis and true hermaphroditism: RSPO1 gene.
    • Cryptic translocations involving SRY on Y and X chromosomes.
    • Mosaicism for XX and cell lines with Y or Y material.
    • 46,XX sex reversal 4: NR5A1 gene.

Other sex chromosome DSDs

  • 45,X
  • 47,XXY
    • Klinefelter syndrome and variants.
  • 45,X/46,XY
    • Mixed gonadal dysgenesis and variants.

Diagnosis

For information about testing, see Presentation: Neonate with ambiguous genitalia.

Inheritance and genomic counselling

Genomic counselling for individuals with a DSD will vary depending on the specific condition or associated gene.

Genomic testing of both the affected individual and their parents is recommended, particularly as the phenotypic spectrum may be wide and mildly affected parents may not have presented clinically.

Management

Assessment, investigation and management of DSDs should be delivered via a multidisciplinary team, including endocrinologists, urologists, gynaecologists, psychologists and geneticists. A pragmatic approach is needed, targeted toward the underlying diagnosis and any associated complications.

Resources

For clinicians:

References:

For patients

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  • Last reviewed: 14/05/2025
  • Next review due: 14/05/2027
  • Authors: Dr Lianne Gompertz
  • Reviewers: Dr Emile Hendriks, Dr Eleanor Hay