Early manifestations of testicular dysgenesis in children: pathological phenotypes, karyotype correlations and precursor stages of tumour development

Abstract

Testicular dysgenesis derives from abnormal gonadal development caused by chromosome aberrations/mosaicisms or mutations/deletions in SRY or other genes responsible for testicular differentiation. Dysgenetic male pseudohaermaphroditism has bilateral dysgenetic testes characterized by a cortical network of anastomosing seminiferous cords that penetrate a thin albuginea. In asymmetric gonadal differentiation (or Mixed Gonadal Dysgenesis) a dysgenetic testis associates with a streak gonad with primitive sex cords embedded in an ovarian-like stroma. Uni- or bilateral ovotestes identify true haermaphroditism. Fluorescent in situ hybridisation studies demonstrate that the sex chromosomes of mosaic patients do not distribute homogeneously in asymmetric gonads. 45,X lines predominate over 46,XY in streak gonads, while the relationship between these two is more equivalent in dysgenetic testes, suggesting that testicular or streak differentiation is related to the balance between X0 and XY lines. Testicular dys-genesis is more severe when there is a frank predominance of X0 or XX cells. Higher percentages of XY cells coincide with lesser degrees of dysgenesis. DNA densitometry indicate a higher incidence of neoplastic transformation than previously anticipated. Various specimens showed clear aneuploid histograms but no clear indication of a cytological CIS phenotype. There was a wide cytological variation in aneuploid germ cells, ranging from normally looking big infantile spermatogonia to gonocyte/CIS cells. Aneuploidy probably precedes the full expression of the CIS phenotype. In case of doubt we recommend DNA densitometry to either confirm or discard their neoplastic nature. The earliest recognizable change in germ cell tumorigenesis is probably the polyploidisation of fetal germ cells, followed by the expression of the CIS phenotype in isolated germ cells scattered along infantile seminiferous tubules that later proliferate to give an adult type CIS pattern.

Distribution of Y-chromosome-bearing cells in gonadoblastoma and dysgenetic testis in 45,X/46,XY infants

“…21 The well-known syndromes associated with a risk for tumor development are: mixed gonadal dysgenesis, some patients with Turner phenotype and in several cases of 46,XY male pseudohermaphroditism. [2][3][4][5][6][7] There is also a reported case of this type of tumor in a 46,XX/46,XY true hermaphrodite. 6 The tumor development in these patients had been associated with the presence of normal or abnormal Y-chromosomes, molecular evidence for Y-derived sequences and intrabdominal location of the abnormal gonads.…”

“…6 The tumor development in these patients had been associated with the presence of normal or abnormal Y-chromosomes, molecular evidence for Y-derived sequences and intrabdominal location of the abnormal gonads. 3,4,7,8,18 The age at diagnosis is variable ranging from birth to the fourth decade; around 94% of cases Distribution of Y-chromosome-bearing cells R Peña-Alonso et al reported in the literature was diagnosed during the second or third decades of life. 22 Data in the literature revealed 10 cases where the tumor developed during childhood, five of them had a 45,X/ 46,XY mixed gonadal dysgenesis and the diagnosis was performed only in one case at 9 months old while the rest were diagnosed around 10 years of age.…”

“…This unique gonadal neoplasm was described by Scully 1 in 1957 as a benign tumor that affects mostly a subset of patients with intersex disorders. The syndromes associated with a clear risk for tumor development are mixed gonadal dysgenesis, 1-3 some patients with Turner phenotype, 4 occasionally in 46,XY male pseudohermaphroditism [2][3][4][5] and there is also a reported case in a 46,XX/46,XY true hermaphrodite. 6 Tumor development in these patients is associated with the presence of either normal or abnormal Y-chromosomes or molecular evidence for Y-derived sequences and intrabdominal location of the abnormal gonad.…”

“…6 Tumor development in these patients is associated with the presence of either normal or abnormal Y-chromosomes or molecular evidence for Y-derived sequences and intrabdominal location of the abnormal gonad. 3,7,8 Histologically, the tumor is composed of well-circumscribed round to oval nests with a mixture of germ cells and sex-cord-type cells resembling immature Sertoli or granulosa cells that often show central calcification. 9 Gonadoblastoma per se does not show invasive behavior but 30% of the specimens demonstrate evidence of overgrowth by the germinal component.…”

Origins and molecular biology of testicular germ cell tumors

“…[37][38][39][40][41][42] 43 have shown a strong correlation between the presence of the Y chromosome and the severity of the gonadal dysgenesis. Gonadoblastoma acts as an 'in situ' precursor in these patients.…”