disorders of sexual development

Digital cases

 Case 1 (HPC:1)
 Case 6 (HPC:6)
 Case 27 (HPC:27)
 Case 41 (HPC:41)
 Case 53 (HPC:53)
 Case 156 (HPC:156)
 Case 161 (HPC:161)
 Case 10645: caudal regression syndrome with lumbosacral agenesis

Definition: Disorders of sexual differentiation (DSDs) have been defined as “congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical”.

DISORDERS OF SEX development (DSDs) or intersex disorders refer to conditions of incomplete or disordered genital or gonadal development leading to a discordance between genetic sex, gonadal sex, and phenotypic sex.

Together, DSDs form a complex entity of heterogeneous etiology that affect the four different dimensions (genetic sex, gonadal sex, phenotypic sex, and behavioral sex) of sex development.

From a clinical as well as a pathological point of view, the distinction between disorders of gonadal dysgenesis (GD), which affect the level of gonadal sex on the one hand, and syndromes of hypervirilization and undervirilization, which affect the level of phenotypic sex on the other, is of particular importance.

Types

 disorders of genital differentiation (disorders generally associated with a normal chromosome constitution and normal gonad)

• FEMALE PSEUDOHERMAPHRODITISM (FEMALE INTERSEX)
  • Fetal defect
    • Adrenogenital syndrome (testosterone overproduction due to adrenocorticoid insuffi ciency)
      • 21α-Hydroxylase defi ciency
      • 11β-Hydroxylase defi ciency
    • Placental aromatase defect
  • Maternal infl uence
    • Maternal ingestion of progestins or androgens
    • Maternal virilizing tumor

• MALE PSEUDOHERMAPHRODITISM (MALE INTERSEX)
  • Primary gonadal defects
    • Testicular regression syndrome (gonadal destruction)
    • Leydig cell agenesis
      • Defective hCG-LH receptor
    • Defects in testosterone synthesis
      • Testosterone and adrenocorticoid insufficiency
        • Defect in cholesterol synthesis (Smith–Lemli–Opitz syndrome)
        • 20,22-Desmolase defi ciency (StAR deficiency)
        • 3β-Hydroxylase dehydrogenase deficiency
        • 17α-Hydroxylase deficiency
      • Testosterone insufficiency only
        • 17,20-desmolase deficiency
        • 17β-Hydroxysteroid (17-ketosteroid reductase) dehydrogenase defi ciency
      • Persistent müllerian duct syndrome (defect in müllerian inhibiting substance system)
  • End-organ defects
    • Androgen receptor binding deficiency
      • Androgen insensitivity syndrome (testicular feminization)
      • Incomplete androgen insensitivity syndrome (Reifenstein syndrome)
    • Peripheral androgen transformation defi ciency
      • 5α-Reductase deficiency

 disorders of sex determination (disorders generally associated with an abnormal sex chromosome constitution leading to abnormal gonadal
formation)

• SEXUAL AMBIGUITY INFREQUENT
  • Klinefelters syndrome (XXY)
  • Turners syndrome and Turner-like (XO and X mosaicism)
  • XX male (sex reversal)
  • Pure gonadal dysgenesis, bilateral
  • Disorders of Wilms tumor gene (WT1)
    • Denys–Drash syndrome
    • Frasiers syndrome

• SEXUAL AMBIGUITY INFREQUENT
  • XY disorder of sex development (DSD) (mixed gonadal dysgenesis (MGD)), including
    • Turner-like (some forms)
    • Dysgenetic male pseudohermaphroditism
  • XY male to female sex reversal
    • Steroidogenic Factor 1 (SF1) abnormality
    • Deleted chromosome 9p
  • True hermaphroditism

Phenotypes

 Female pseudohermaphroditism (46,XX DSD) causes a female genotype and two ovaries for gonads, but their external genitalia show a variable degree of virilization.
 Male pseudohermaphroditism (46,XY DSD) causes a male genotype and two testes for gonads, but their external genitalia show a variable degree of feminization.
 True hermaphrodites (ovotesticular DSD) causes both testicular and ovarian tissues in the gonads.

In patients with pure gonadal dysgenesis (PGD), both gonads are streak gonads (ie, dysfunctional gonads without germ cells). Patients with mixed gonadal dysgenesis (MGD) have a testis on one side and a streak gonad on the other.

Chromosomal classifcation

 XY intersex
 XX intersex

Morphological classification

 true hermaphrodism
 MGD
 pseudohermaphroditisms

• male pseudohermaphroditism
• female pseudohermaphroditism

Etiology

 chromosomal diseases
 monogenic diseases
 caudal regression syndrome

Nomenclature

A new nomenclature for disorders of sexual differentiation has been proposed by the International Consensus Conference on Intersex (organized by the Lawson Wilkins Pediatric Endocrine Society) and the European Society for Pediatric Endocrinology, and takes into consideration developments in molecular genetics, ethical issues, and the perception of existing terms as potentially pejorative.

The term disorders of sex development (DSDs) was proposed to describe the entire group. The consensus group proposed the classification of DSDs into:
 sex chromosome DSDs
 46,XY DSDs
 46,XX DSDs

See also

 ambiguous genitalia
 DSD-associated tumors

Reviews (Biology)

 MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med. 2004 Jan 22;350(4):367-78. PMID: 14736929

 Vaiman D, Pailhoux E. Mammalian sex reversal and intersexuality: deciphering the sex-determination cascade. Trends Genet. 2000 Nov;16(11):488-94. PMID: 11074290

 Behrman: Nelson Textbook of Pediatrics, 16th ed., Chapter 598 - Hermaphroditism (Intersexuality), p. 1760-1767.

 Cotinot C, Pailhoux E, Jaubert F, Fellous M. Molecular Genetics of Sex Determination, Seminars in Reproductive Medicine, 2002; p. 157-168.

 Hutcheson J. Ambiguous Genitalia and Intersexuality, eMedicine Journal, 2002, 3(8); p.1-25.

 McGregor L et al. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein, Nature Genetics, 2003, 34(2); p. 203-208.

 Sultan C, Paris F, Jeandel C, Lumbroso S, Benoît Galifer R. Ambiguous Genitalia in the Newborn, Seminars in Reproductive Medicine, 2002; p. 181-188.

References

 Houk CP, Lee PA 2005 Intersexed states: diagnosis and management. Endocrinol Metab Clin North Am 34:791–810. PMID: 16085171

 Grumbach MM, Hughes IA, Conte FA 2003 Disorders of sex differentiation. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KM, eds. Williams textbook of endocrinology. 10th ed. Philadelphia: W.B. Saunders (Elsevier); 842–1002

 New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD). Hersmus R, de Leeuw BH, Wolffenbuttel KP, Drop SL, Oosterhuis JW, Cools M, Looijenga LH. Mol Cell Endocrinol. 2008 Sep 10;291(1-2):1-10. PMID: 18403106

 NabhanZM, Lee PA. Disorders of sex development. Curr Opin Obstet Gynecol 2007;19:440–445.

 JhaA. Intersex (genital ambiguity). Available at: http://www.bui.ac.uk/Tutorials/Intersex.htm. Accessed October 1, 2007.

 LooijengaLH, Hersmus R, Oosterhuis JW, Cools M, Drop SL, Wolffenbuttel KP. Tumor risk in disorders of sex development (DSD). Best Pract Res Clin Endocrinol Metab 2007;21:480–495.

Books

 Oxford Medical Databases

 London Dysmorphology Database

 Potter’s Pathology of the Fetus and Infant, Chapter 27 - Reproductive System, editor Enid Gilbert-Barness, p. 1202-1241.

 Walsh: Campbell’s Urology, 8th ed., Chapter 68 - Sexual Differentiation: Normal and Abnormal, 2002, p. 2395-2423.