Ambiguous 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 ambiguous genitalia are called disorders of sex development (DSD).
DSD are congenital conditions that most commonly present in the newborn period.
DSD can be classified as sex chromosome DSD, 46,XY DSD, or 46,XX 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 characterised by excess exposure to androgens. Over 95% of causes of ambiguous 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 aetiologies and usually requires a more extensive diagnostic evaluation.
The initial management of a neonate with ambiguous 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 paediatric endocrinology, genetics, and surgery, and with appropriate psychiatric/psychological support. For many DSDs, long-term surgical and psychosexual outcomes remain uncertain.
Disorders of sex development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. A subset of children with DSD present at birth with ambiguous genitalia (i.e., a genital phenotype that is neither clearly male nor clearly female) and without other dysmorphic features. Many causes have a genetic basis. A very rare exception may occur when there is virilisation of a 46,XX fetus by maternal virilising tumours or maternal exposure to androgenic drugs.
This topic addresses the initial approach to neonates with ambiguous genitalia who are not identified as having a specific chromosomal syndrome in which ambiguous genitalia may be one of a number of presenting features.
History and exam
- ambiguous genitalia with no palpable gonads
- ambiguous genitalia with one palpable gonad
- ambiguous 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
- 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 gonadotrophin (hCG) stimulation test
- Müllerian-inhibiting substance (MIS) or anti-Müllerian hormone (AMH)
- urine steroid profile
Justin H Davies, MD, FRCPCH, MRCP
Consultant Paediatric Endocrinologist
Honorary Senior Lecturer
University of Southampton
JD is chair of the British Society for Paediatric Endocrinology and Diabetes and a medical advisor to the Child Growth Foundation. He has received a travel bursary from Novo Nordisk and grants from the European Society for Paediatric Endocrinology and the Child Growth Foundation.
Gemma Watts, BMS, MRCPCH
Specialist Registrar in Paediatric Endocrinology
Department of Paediatrics
University Hospitals Southampton NHS Trust
GW declares that she has no competing interests.
Dr Justin Davies and Dr Gemma Watts would like to gratefully acknowledge Dr Ingrid A. Holm, a previous contributor to this topic. IAH declares that she has no competing interests.
Paul Saenger, MD, MACE
Professor of Pediatrics
Department of Pediatrics (Endocrinology)
Montefiore Medical Center
Albert Einstein College of Medicine
PS declares that he has no competing interests.
Mary M. Lee, MD
Professor of Pediatrics and Cell Biology
Vice-Chair of Academic Affairs in Pediatrics
Pediatric Endocrine Division
UMass Medical School
MML declares that she has no competing interests.
Patricia Y. Fechner, MD
Associate Professor Pediatrics
University of WA
Medical Director of DSD Program
Seattle Children’s Hospital
PYF declares that she has no competing interests.
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