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Disorders of sexual differentiation


Turki Al-Hussain, M.D.

Last author update: 1 September 2012
Last staff update: 29 November 2022

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PubMed Search: Disorders of sexual differentiation

Turki Al-Hussain, M.D.
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Table of Contents
Androgen insensitivity | Gonadal dysgenesis-mixed | Gonadal dysgenesis-pure | Klinefelter syndrome | Male pseudohermaphroditism | Persistent Müllerian duct | True hermaphroditism
Cite this page: Al-Hussain T. Disorders of sexual differentiation. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/testisdisordersofsexualdiff.html. Accessed April 19th, 2024.
Androgen insensitivity
Definition / general
  • Either XY or XXY
  • Called testicular feminization if complete
  • Most frequent cause of male pseudohermaphroditism
  • Lack of androgen receptor due to mutations in gene on X chromosome

Clinical features
  • Phenotypic female, tall with well formed breasts, absent / scanty pubic and axillary hair, shallow vagina and lack of upper vagina because anti-Müllerian hormone (AMH) causes Müllerian duct regression
  • Patients also have bilateral cryptorchidism with intraabdominal, inguinal or labial testes; usually no Wolffian or Müllerian derivatives
  • Recommend gonadectomy by puberty since associated with germ cell tumors (30% by age 50)

Case reports

Gross description
  • Tanish brown testes with multiple white nodules of Sertoli cells and Wolffian / Müllerian duct cysts at lateral pole of testis

Microscopic (histologic) description
  • Small seminiferous tubules without lumina composed of Sertoli cells only, usually immature, with sparse spermatogonia, marked Leydig cell hyperplasia (often without Reinke crystals), ovarian type stroma; nodules are probably hamartomas of Sertoli cells
Gonadal dysgenesis-mixed
Definition / general
  • Testis plus contralateral streak gonad, testis and contralateral gonadal agenesis, hypoplastic gonads with tubules in one gonad or streak gonad with
  • Müllerian structures present since no / minimal AMH produced
  • Usually bilateral fallopian tubes
  • Usually incomplete masculinization of external genitalia, poor development of ipsilateral Wolffian duct structures
  • External genitalia are male, female or ambiguous (ambiguous in most patients, two - thirds raised as female)
  • Phenotypic females may develop signs of virilization at puberty
  • Karyotypes: 45 X0 / 46 XY, 46 XY most common
  • Associated with low immunoglobulin levels, aberrant bony development of inner ear structures, cardiovascular and renal anomalies

Treatment
  • Early bilateral gonadectomy advocated if Y chromosome material is present to prevent gonadoblastoma (one - third) or other germ cell tumors; also to prevent virilization if patient is raised as female (Arch Pathol Lab Med 1990;114:679)

Microscopic (histologic) description
  • Tubules with mild hypospermatogenesis to total sclerosis (Mod Pathol 2002;15:1013, Hum Pathol 1982;13:700)
  • Streak gonad has ovarian stroma without primordial ovarian follicles
  • Streak ovary has primitive sex cord-like structures within ovarian type stroma, variable germ cell components, resembles either gonadoblastoma, granulosa cell or Sertoli cell tumors

Differential diagnosis
Gonadal dysgenesis-pure
Definition / general
  • Also called Swyer syndrome
  • Female phenotype and female genital appearance, normal Müllerian structures
  • Bilateral streak gonads, so no hormonal or reproductive potential
  • 46 XY but no testicular tissue; no evidence of Turner syndrome
  • Early bilateral gonadectomy is recommended due to high incidence of gonadoblastoma and dysgerminoma (J Pediatr Urol 2011;7:72)

Case reports

Gross images

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Woman with dysgerminoma and streak gonad



Microscopic (histologic) images

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Dysgerminoma

Streak gonad

Klinefelter syndrome
Definition / general
  • 47XXY, reduced body and pubic hair, gynecomastia in 40 - 80%, high FSH, variable LH
  • Increased risk of breast cancer and extragonadal germ cell tumor

Gross description
  • Small, firm testes

Microscopic (histologic) description
  • Reduced number of intratubular germ cells, some tubules are Sertoli cell only
  • Also tubular sclerosis, Leydig cell nodules (appear hyperplastic due to tubular atrophy), focal spermatogenesis rarely seen

Electron microscopy description
Male pseudohermaphroditism
Definition / general
  • XY, testes present, phenotype ambiguous or female

Congenital adrenal hyperplasia
  • Autosomal recessive, due to various enzymatic defects that cause different patterns of synthesis of glucocortical, mineralocorticoid and sex hormone synthesis
  • Genetic males have cryptorchidism, viable Wolffian duct structures, female or ambiguous genitalia, no Müllerian duct structures
  • Testes resemble cryptorchid testes
  • May have bilateral Leydig cell hyperplasia with deficiencies of 21-hydroxylase, 11β hydroxylase, 17α hydroxylase, 3β hydroxysteroid dehydrogenase
  • Treat with corticosteroids or surgical excision of testes

Dysgenetic male pseudohermaphroditism
  • Bilateral dysgenetic testis, Müllerian structures, cryptorchidism, inadequate virilization
  • May be XO / XY mosaics
  • Infertile, no spermatogenesis
  • 30% incidence of testicular tumors (J Urol 1978;119:525)
Persistent Müllerian duct
Definition / general
  • Rare form of male pseudohermaphroditism, Müllerian duct structures persist due to lack of AMH effect due to either mutation in AMH gene on chromosome 19p13.3 or abnormality of receptor gene on chromosome 12q13
  • X linked or autosomal recessive
  • Phenotypic male, normal external genitalia, unilateral or bilateral cryptorchidism, may have empty hemiscrotum, normal Wolffian duct derivatives; however also have Müllerian duct derivatives (uterus and usually 2 fallopian tubes) within an inguinal hernia
  • 2 forms:
    • Unilateral cryptorchidism and contralateral hernia
    • Bilateral cryptorchidism, uterus in pelvis, both testes embedded in broad ligament
  • 15% risk of germ cell tumors, including intratubular germ cell neoplasia

Case reports

Differential diagnosis
True hermaphroditism
Definition / general
  • Unequivocal ovarian and testicular tissue in same patient, occuring as either bilateral or unilateral ovatestes or as a testis opposite an ovary, regardless of karyotype
  • Ovary is usually normal; testis usually lacks spermatogonia
  • No streak gonads present; usually no associated gonadoblastomas
  • Usually no other developmental malformations and patients may have normal sexual and reproductive functions

Treatment
  • After assigning gender, remove inappropriate gonad and biopsy remaining tissue

Microscopic (histologic) description
  • Ovarian compartment has numerous primordial follicles with primary oocytes and a few primary or antral follicles (Mod Pathol 2002;15:1013)

Differential diagnosis
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