Atypical genitalia (i.e., a genital phenotype that is neither clearly male nor female) are caused by the atypical development of chromosomal, gonadal, or anatomical sex. The complex group of disorders that cause atypical genitalia are called differences of sex development (DSD).
Sex chromosome DSD results from the atypical complement of sex chromosomes, and includes syndromes such as Turner syndrome (45,X with one absent sex chromosome) and Klinefelter syndrome (XXY with one additional X chromosome). Mosaicism occurs when more than one type of chromosomal arrangement is present (e.g., 45,X/46,XY).
46,XX DSD are conditions characterized by excess exposure to androgens. Over 95% of causes of atypical genitalia with a 46,XX genotype are due to congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency.
46,XY DSD can be due to several etiologies and usually requires a more extensive diagnostic evaluation.
The initial management of a neonate with atypical genitalia is a social and clinical emergency. The local team has a key role in coordinating the initial assessment and investigations, and supporting parents. It is important there is early discussion with a more specialist multidisciplinary team with expertise in pediatric endocrinology, genetics, and surgery, and with appropriate psychiatric/psychological support. For many DSDs, long-term surgical and psychosexual outcomes remain uncertain.
Differences of sex development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. DSD most commonly present in the newborn period and can be classified as sex chromosome DSD, 46,XY DSD, or 46,XX DSD. A subset of children with DSD present at birth with atypical genitalia and without other dysmorphic features. Many causes have a genetic basis. A very rare exception may occur when there is virilization of a 46,XX fetus by maternal virilizing tumors or maternal exposure to androgenic drugs.
This topic addresses the initial approach to neonates with atypical genitalia who are not identified as having a specific chromosomal syndrome in which atypical genitalia may be one of a number of presenting features.
History and exam
Key diagnostic factors
- atypical genitalia with no palpable gonads
- atypical genitalia with one palpable gonad
- atypical genitalia with bilaterally palpable gonads
- penile length <2.5 cm in a phenotypic male
- clitoris >1 cm in a phenotypic female
- hypospadias and undescended testes or separation of scrotal sacs
- urethral opening at base of phallus
Other diagnostic factors
- hypotension and vomiting
- dysmorphic facial features
- family history
1st investigations to order
- chromosome analysis (karyotype)
- serum electrolytes and glucose
- pelvic ultrasound
Investigations to consider
- serum 17 hydroxyprogesterone
- plasma renin activity
- serum 11 deoxycortisol and 11 deoxycorticosterone
- serum testosterone
- serum dihydrotestosterone
- serum LH and follicle-stimulating hormone (FSH)
- adrenocorticotropic hormone (ACTH) stimulation test
- human chorionic gonadotropin (hCG) stimulation test
- anti-Müllerian hormone (AMH)
- urine steroid profile
all neonates presenting with atypical genitalia
46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (at presentation)
45,X/46,XY mixed gonadal dysgenesis
46,XX: congenital adrenal hyperplasia secondary to 21 hydroxylase deficiency (following sex assignment)
45,X/46,XY mixed gonadal dysgenesis
- Micropenis due to another cause
- Unilateral undescended testis (cryptorchidism)
- Guidelines on paediatric urology
- UK guidance on the initial evaluation of a suspected difference or disorder of sex development (revised 2021)
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