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Differences of sex development

Nature Reviews Disease Primers volume 11, Article number: 54 (2025) Cite this article

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Abstract

Differences of sex development (DSD) represent a group of congenital conditions that affect human sex development and maturation owing to discrepancies of chromosomal, gonadal and phenotypic sex. The Chicago consensus classifies DSD as sex chromosome DSD, 46,XY DSD and 46,XX DSD, with subclassifications according to gonadal determination into testes and ovaries and hormone-dependent differentiation of Müllerian and Wolffian embryonic structures into female-typical or male-typical internal and external sex organs. DSD may occur as an isolated condition or as part of a complex syndrome. Diagnosis is based on clinical characteristics, imaging studies, hormonal measurements and genetic investigations. Management includes lifelong psychosocial support, hormonal treatments and surgical interventions that require personalization for each case as DSD encompasses a wide variety of aetiologies and presentations. This personalization must also consider individual values and preferences to ensure that clinical care is tailored to meet the unique needs and circumstances of each person, ideally provided by a care team with diverse specialities. This care involves psycho-educational counselling on the condition and its consequences, considering family and cultural norms. Additional efforts are needed to bridge gaps in knowledge related to diagnosis, management and long-term outcomes. Enhancing our understanding of the distinctions between sex and gender in societies is essential as greater awareness will inform and enrich public debates.

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Fig. 1: Classification of DSD based on karyotype and diagnostic category leading to a specific diagnosis.
Fig. 2: Associated organ anomalies and comorbidities of DSD.
Fig. 3: Sex determination of the human ovaries and testes from the bipotential gonads at 4–16 weeks of gestation.
Fig. 4: Sex differentiation.
Fig. 5: 46,XX ovotesticular DSD.
Fig. 6: Sex steroid hormone biosynthesis and associated DSD.
Fig. 7: Diagnostic algorithm for 46,XY DSD with atypical genitalia at birth.
Fig. 8: Diagnostic algorithm for 46,XX DSD.
Fig. 9: Development of GCTs in DSD and their proposed management.
Fig. 10: Multidisciplinary care at diagnosis and across the lifespan.
Fig. 11: Schematic representation of a risk stratification model and recommendations for clinical follow-up.
Fig. 12: Research priorities in DSD: insights from data requests, health-care providers and patient perspectives.

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Acknowledgements

C.E.F. acknowledges the support by Swiss National Science Foundation grant 320030_197725. The authors thank Melissa D. Gardner for supporting manuscript editing.

Author information

Authors and Affiliations

  1. Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    Syed Faisal Ahmed

  2. Caring & Living as Neighbours (CLAN), Denistone, New South Wales, Australia

    Kate Armstrong

  3. Division of Urology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Earl Y. Cheng

  4. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Earl Y. Cheng

  5. Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium

    Martine Cools

  6. Department of Paediatric Endocrinology, Ghent University Hospital, Ghent, Belgium

    Martine Cools

  7. Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, Victoria, Australia

    Vincent Harley

  8. Department of Internal Medicine, LIM/42, Discipline of Endocrinology, University of São Paulo Medical School, University of São Paulo, São Paulo, Brazil

    Berenice B. Mendonca

  9. Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden

    Anna Nordenström

  10. Paediatric Endocrinology Unit, Karolinska University Hospital, Stockholm, Sweden

    Anna Nordenström

  11. Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños R. Gutiérrez, Buenos Aires, Argentina

    Rodolfo Rey

  12. Susan B. Meister Child Health and Evaluation Research Center and the Division of Paediatric Psychology, Department of Paediatrics, University of Michigan Medical School, Ann Arbor, MI, USA

    David E. Sandberg

  13. Division of Paediatric Endocrinology, Department of Paediatrics, Faculty of Medicine, Diponegoro University, Semarang, Indonesia

    Agustini Utari

  14. Paediatric Endocrinology, Diabetology and Metabolism, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    Christa E. Flück

  15. Department of BioMedical Research, University of Bern, Bern, Switzerland

    Christa E. Flück

Authors
  1. Syed Faisal Ahmed
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  2. Kate Armstrong
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  3. Earl Y. Cheng
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  4. Martine Cools
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  5. Vincent Harley
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  6. Berenice B. Mendonca
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  8. Rodolfo Rey
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  9. David E. Sandberg
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  11. Christa E. Flück
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Contributions

Introduction (S.F.A.); Epidemiology (S.F.A.); Mechanisms/pathophysiology (M.C., V.H. and R.R.); Diagnosis, screening and prevention (M.C. and C.E.F.); Management (E.Y.C., B.B.M., A.N. and D.E.S.); Quality of life (D.E.S., K.A. and A.U.); Outlook (S.F.A., K.A., A.U. and C.E.F.); overview of the Primer (S.F.A. and C.E.F.).

Corresponding author

Correspondence to Christa E. Flück.

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Nature Reviews Disease Primers thanks O. Hiort, M. Fukami and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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The authors affirm that patient participants provided informed consent for publication of their experiences.

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Glossary

Adrenoleukodystrophy

Rare X-linked recessive inherited disorder, characterized by neurological symptoms and dysfunctional adrenal glands.

Androgen insensitivity syndrome

Differences of sex development condition characterized by decreased or absent androgen signalling due to a genetic defect affecting the binding of testosterone or dihydrotestosterone to the androgen receptor.

Bipotential gonads

Undifferentiated gonads that have the capacity to develop into either ovaries or testes.

Chordee

A congenital condition that affects penile function and appearance, causing a curvature in the penis during erection.

Cryptorchidism

Failure of testes to descend into the scrotum.

Dysgerminoma

Malignant tumour arising from primordial germ cells in the ovary or dysgenetic gonad.

Gender identity

A person’s basic subjective sense of self as a male, as a female or some other gendered identity, for example, an ‘intersex’ identity. Gender identity develops over time and is not directly a function of genes or prenatal sex hormone exposure.

Gender role

Behaviours, attitudes and personality traits that a society, in a given culture and historical period, designates as masculine or feminine, and that are more ‘appropriate’ to or typical of the male or female social role.

Gonadal dysgenesis

Differences of sex development condition characterized by the loss of primordial germ cells and abnormal gonadal development during embryonic development.

Granulosa cells

Female-supporting cell lineage in the ovary.

Klinefelter syndrome

A condition affecting only males that occurs when an extra X chromosome is present (47,XXY).

Labioscrotal folds

A paired structure that is present during the indifferent stage of external genitalia development and is responsible for the formation of the labia majora in females and the scrotum in males.

Leydig cells

Steroid-producing cells in the testis.

Minifascicular peripheral neuropathy

A rare autosomal recessive inherited condition characterized by the presence of small fascicles in the peripheral nervous system.

Non-seminoma

Malignant tumour derived from seminoma or its precursor lesion through reprogramming of the seminomatous cells into an embryonal carcinoma cell.

Sertoli cells

Male-supporting cell lineage in the testis.

Turner syndrome

A condition affecting only females that occurs when one of the X chromosomes (sex chromosomes) is missing or partially missing.

Urethrovaginal fistula

A condition characterized by urine leakage from the urethra into the vagina due to an abnormal connection between the urethra and the vagina.

Vaginal stenosis

An abnormal narrowing of the vaginal canal.

Virilization

A condition in which females develop exaggerated male traits such as excessive facial hair.

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Ahmed, S.F., Armstrong, K., Cheng, E.Y. et al. Differences of sex development. Nat Rev Dis Primers 11, 54 (2025). https://doi.org/10.1038/s41572-025-00637-y

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