mixed gonadal dysgenesis

Digital slide

 HPC:33 : Mixed gonadal dysgenesis
 HPC:114 : Mosaicism 46,XY/45,X0 - Mixed gonadal dysgenesis
 HPC:398 : Mixed gonadal dysgenesis

Definition: The presence of a testis on one side and a streak gonad on the other establishes the diagnosis of mixed gonadal dysgenesis (MGD), or asymetrical DSD (asymetrical disorder of sexual differentiation).

Because of this characteristic appearance, some investigators prefer the name ‘asymmetric gonadal dysgenesis’ rather than ‘mixed gonadal dysgenesis’.

Mixed gonadal dysgenesis (MGD) is one of the most frequent causes of male sexual ambiguity.

About two-thirds of affected individuals are raised as females and the remainder as males, in part for psychological and cultural reasons and so as to prevent the future development of cancer, which is not uncommon.

Mixed gonadal dysgenesis (MGD) can also be considered as a type of asymmetrical gonadal dysgenesis (one side is more developed than the other):

 (a) testis plus contralateral streak gonad
 (b) testis and contralateral gonadal agenesis
 (c) hypoplastic gonads with tubules in one gonad
 (d) streak gonad with contralateral tumor

The gonads can consist of a macroscopic testis and a streak gonad; or variants, including bilateral testes and bilateral streak gonads or tumors. Functionally, the gonads were incompetent.

Etiology

 45,X0/46,XY mosaicism (dysgenetic male pseudohermaphroditism)
 46,XY intersex
 partial deletions of chromosome Y

A variety of different genetic abnormalities appear to result in MGD, thus leading to its phenotypic heterogeneity.

Partial deletions of both the short and long arms of chromosome Y have been detected in these individuals.

Most cases where no detectable Y chromosomal anomaly is observed by conventional chromosome analysis have a Y fragment found when additional testing is performed.

Testes

 1) fail to completely inhibit mullerian development (absent or incomplete AMH action)
 2) fail to support full differentiation of mesonephric duct structures (wwolffian structures)
 3) fail to adequately masculinize development of the external genitalia
 4) often failed to mediate their own descent, resulting in asymmetry of the internal and external genitalia.

Clinical synopsis

Mixed gonadal dysgenesis (MGD) is a heterogeneous syndrome with a 45,X/46,XY or 46,XY karyotype, persistent müllerian duct structures, a dysgenetic testis, and a contralateral streak gonad.

Mixed gonadal dysgenesis (MGD) is one of the most frequent causes of male sexual ambiguity.

The functional deficit imposed by the abnormal testis is expressed as incomplete inhibition of müllerian development (incomplete AMH action), incomplete differentiation of wolffian duct structures (mesonephric ducts), and incomplete male development of the external genitalia.

Often, incomplete mediation of testicular descent occurs, resulting in both internal and external asymmetry of the genitalia and a mixture of male and female features in an individual in whom neither gonad is normal.

Clinically, MGD is usually detected in the neonate because of ambiguous external genitalia. Frequently, a palpable testis bulges through an indirect inguinal hernia or descends completely into the labioscrotal fold, resulting in asymmetry of the genital swellings. This clinical appearance prompted some earlier investigators to name the syndrome ‘asymmetric gonadal dysgenesis’.

Gonads - If the gonads are intraabdominal, the labioscrotal folds may appear as normal labia or as empty scrotal sacs. The condition is likely to go unrecognized unless the clitoris is sufficiently enlarged to mandate investigation, which is common. The gonad that descends is usually a testis, and the streak gonads are always intraabdominal unless dragged into a ‘hernia uteri inguinale’.

Paramesonephric ducts - Organs derived from the müllerian ducts (paramesonephric ducts) persist in 95% of cases. The uterus is usually infantile or rudimentary, but occasionally may be normal. The fallopian tubes are frequently bilateral. If a testis is grossly near normal size and well differentiated, the fimbria of the ipsilateral tube may be absent, but in only one-third of cases is the ipsilateral tube entirely absent.

Mesonephric ducts - Organs of wolffian duct derivation (mesonephric ducts) may also be present, but the frequency is variable. An epididymis is identified in two-thirds of cases and is usually present on the side where there is a testis. The vas deferens is encountered less frequently. The seminal vesicle is identified only rarely, probably because tissue near the bladder/prostate region is not usually removed.

Phenotypic overlaps

Given the overlap, the syndrome of MGD should be enlarged to incorporate some patients with bilateral streak gonads, streak-like areas but with tubules (described
above as 46,XY type pure gonadal dysgenesis) or bilateral abnormal testes with a mosaic 45,X/46,XY karyotype (dysgenetic male pseudohermaphroditism) because the clinical, pathologic, and chromosomal features of these syndromes closely resemble each other. In turn, some patients with MGD exhibit the phenotypic features of a Turner-like syndrome.

Pathology

The gonad may be a testis or a streak gonad.

 Streak gonad. Intraoperative examination shows a small, triangular, whitish streak gonad attached to the fallopian tube. Because of its small size, a streak gonad is not usually seen at imaging. Streak gonads may be partially differentiated toward testis, or suggestion of differentiation toward ovary with gonadal-type stroma and even a very rare primordial follicle, but not ovary which requires the presence of differentiation with follicles in at least the antral stage.

 Bilateral gross testes, frequently of an asynchronous degree of maturity, are found in about 15% of cases whereas a unilateral gross testis is found in 60%.

The testis is consistently abnormal architecturally, its organization being divided into three zones, each of which refl ects the quantity and type of
cellular components present. The three zones, which are described below in detail, include:

 (1) the region of the tunica albuginea or cortex, which exhibits a range of findings from widely spaced seminiferous tubules or differentiation toward streak, usually with ovarian-like stroma to immature zones indeterminate between female and male structures with primary sex cords;
 (2) the medulla, which is composed of normal or near-normal seminiferous
tubules and interstitium;
 (3) a hilar region with poorly differentiated seminiferous tubules that are
only partly differentiated toward testis. It is uncertain whether this zone may represent hypertrophied rete testis.

The superficial cortex may contain seminiferous tubules that are often widely separated by edematous, undifferentiated stroma. Sometimes the tubules penetrate the incompletely formed tunica albuginea and open onto the serosa. Occasionally, broad zones of cortex differentiate slightly toward streaklike
ovary, even displaying rare primordial follicles, but as mentioned above, without more fully developed follicles would still be called a streak (or, as some prefer, a ‘streak-testis’). In some cases it is difficult to distinguish between
female and male structures.

The central zone (medulla) of the macroscopic infant testis is usually architecturally and cytologically normal. Narrow closed seminiferous tubules are lined by Sertoli cells with abundant cytoplasm. The numbers of spermatogonia
vary. Advanced forms of spermatogenic maturation are not observed. Occasionally, the germ cells are seen to lie directly on the basement membrane of the seminiferous tubule rather than being surrounded normally by Sertoli cells. Leydig cells are present in small clusters of varying size. The nuclei of the Leydig cells contain finely dispersed chromatin, and the cytoplasm varies from minimal and amphophilic or slightly basophilic to abundant and eosinophilic. In older
patients, the medulla is atrophic and the tubules are lined only by Sertoli cells. The basement membranes are often thickened. Prominent clusters of Leydig cells fill the interstitium. The tunica albuginea is composed of stroma resembling the stroma of ovarian cortex.

The architecturally disorganized hilar region discloses seminiferous tubules that are swollen by increased numbers of Sertoli cells and are lined by indistinct basement membranes. These tubules also merge with the surrounding stroma, imparting the appearance of a homogeneous blend of Leydig cells, germ cells, Sertoli cells, and an indeterminate type of interstitial stroma. The region resembles neither fetal ovary nor testis. It is uncertain whether some of this region may represent rete testis.

The streak gonads appear similar to those found in Turner syndrome. It has not been observed a gonad that has been identifiable grossly as an ovary or has been shown microscopically to contain Graafi an follicles, corpora lutea or corpora albicantia. However, the presence of rare primordial follicles or, especially as in the fetal ovary, aggregates of germ cells partially surrounded by immature granulosa cells are evidence that a streak gonad can differentiate toward ovary.

Morphologic changes may occur over time in the streak gonads. Myriads of
germ cells present in a streak of an infant may degenerate and disappear by puberty, resulting in a gonad composed exclusively of fibrous tissue and a few rete tubules. Similar changes occur in the streak gonads of Turners syndrome
(45,X karyotype).

Tumors develop in about 10% of patients with mixed gonadal dysgenesis. The most common is the gonadoblastoma. Approximately 30% of gonadoblastomas
are overgrown by a malignant germ cell tumor, usually the germinoma; 8% are overgrown by yolk sac tumor, immature teratoma, embryonal carcinoma or choriocarcinoma.

An occasional gonad may also show proliferative sex-cord elements and resemble a Sertoli cell tumor or disclose nodules suggestive of a juvenile granulosa cell
tumor. Although the gonadoblastoma itself does not metastasize and therefore can be considered as a precancer or an in situ malignancy, the typically malignant behavior of the other tumors makes early prophylactic removal of the gonads in all patients advisable.

Also, to avoid the consequences of onset ofvirilization if the patient is to be raised as a female, it is important that gonadectomy be performed before the patient reaches puberty. The ultimate gender identity that a patient may desire is an area of controversy. Patients who have been treated with long-term administration of estrogen may on occasion develop endometrial carcinoma. Congenital cardiovascular anomalies have also been reported in patients with MGD.

Pathology

Testes with seminiferous tubules usually develop to a moderately advanced state, macroscopically resembling testes, the hilar zone remains architecturally disorganized; the cortex invariably lacks more than a rudimentary tunica albuginea or exhibited partial ovarian differentiation, sometimes even with a rare primordial follicle. Over time, the seminiferous tubules are atrophied and hyalinized.

 streak gonads

• composed of a stroma resembling that of normal ovarian cortex

 bilateral testes

• streak testis: streak tissue identified at periphery of differentiated testis (dysgenetic gonad)

 bilateral streak gonads

• streak gonad: ovarian-type stroma without differentiated gonadal structures (dysgenetic gonad)

 mullerian structures present since no/minimal anti-Mullerian hormone produced
 usually bilateral fallopian tubes; occasionally vas deferens
 external genitalia

• female: clitoromegaly
• male: hypospadias or normal male

 aberrant bony development of inner ear structures
 cardiovascular anomalies
 renal anomalies

 phenotypic males

• short stature
• 90-degree penile torsion
• undescended testis
• chordee without hypospadius
• undescended non-functional streak gonad
• horseshoe kidney (18648333)

 phenotypic females may develop virilization at puberty, often complete; no breast development except with tumors

Biology

 chromatin negative Barr bodies
 karyotypes: 45 X0/46 XY, 46 XY, 45 X0/47 XXY
 elevated FSH
 deficient immunoglobulin levels

Microscopical synopsis

 prepubertal patients: normal immature testis
 at/after puberty:

• tubules exhibit mild hypospermatogenesis to total sclerosis
• streak gonad has ovarian stroma without primordial ovarian follicles
• streak ovary is streak gonad with primordial follicles and primitive sex-cordlike structures with or without germ cell components within the ovarian-type stroma, mimicking gonadoblastoma, granulosa cell tumor or Sertoli cell tumors

 classic form : unilateral streak gonad and unilateral dysgenetic fibrotic testis, retained müllerian ducts and incomplete genital masculanization (testosterone deficiency)

Imaging

Streak gonads are difficult to visualize and characterize at imaging, including US and MR imaging. A gonad with the morphologic appearance of a testis or ovary at US may prove to be a dysgenetic gonad at biopsy.

At minimum, a rudimentary uterus or fallopian tube can be seen on the side with the streak gonad. On the side with the testis, local MIS diffusion prevents development of a fallopian tube.

Tumor predisposition

 high risk for gonadoblastoma (30%) if Y chromosome material is present
 Early removal of gonads will prevent the development of gonadoblastoma and dysgerminoma.

Differential diagnosis

 true hermaphroditism (ovary has numerous primordial follicles containing primary oocytes, nature of internal or external genitalia is not relevant)

Cytogenetics

 45,X/46,XY mosaicism
 most often : 46,X0-46,XY mosaic karyotype
 46,XY karyotype in 40% of patients

See also

 gonadal dysgenesis
 dysgenetic gonad

References

 Mixed gonadal dysgenesis in a 45,X neonate with chromosome Y material in the dysgenetic gonad. Karatza A, Chrysis D, Stefanou EG, Mantagos S, Salakos C. J Pediatr Endocrinol Metab. 2009 Nov;22(11):1083-6. PMID: 20101895

 Dysgenesis of testicular and streak gonads in the syndrome of mixed gonadal dysgenesis: perspective derived from a clinicopathologic analysis of twenty-one cases. Robboy SJ, Miller T, Donahoe PK, Jahre C, Welch WR, Haseltine FP, Miller WA, Atkins L, Crawford JD. Hum Pathol. 1982 Aug;13(8):700-16. PMID: 7106733

 Short stature in a phenotypic male caused by mixed gonadal dysgenesis. Jacobsen CM, Cohen LE. Nat Clin Pract Endocrinol Metab. 2008 Sep;4(9):524-8. PMID: 18648333

 Seminoma and a gonadoblastoma in an infant with mixed gonadal dysgenesis. Haddad NG, Walvoord EC, Cain MP, Davis MM. J Pediatr. 2003 Jul;143(1):136. PMID: 12915842