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Case Report
GONADOBLASTOMA IN A PATIENT WITH 46XY GONADAL DYSGENESIS M. Coculescu*1, N. Poiana2, Corina Rãducanu-Lichiardopol3, Mioara Ionescu4 1Department
of Endocrinology, and 2Department of Obstetrics and Gynecology, University of Medicine and Pharmacy “Carol Davila” Bucharest 3Department of Endocrinology, University of Medicine and Pharmacy, Craiova, 4Department of Pathology“Gh. Polizu” University Hospital, Bucharest, Romania
We present a 18 year old phenotypic female patient who presented for primary amenorrhea. Pelvic ultrasound revealed a hypoplastic uterus and CT scan showed a hypoplastic right gonad and a left gonadal tumor with extrapelvic location. Karyotype was 46XY. Hormonal assessment indicated hypergonadotropic hypogonadism: FSH was 39.69 mUI/ml, estradiol was 28.07 pg/ml, testosterone was 0.17 ng/ml. DHEA level was high – 21 ng/ml. Gonadectomy was performed at 15 years and histologic examination diagnosed left gonadoblastoma and right teratoma in a dysgenetic gonad. The patient had a good postoperatory evolution. Menses were induced with estrogenic and then estroprogestogenic treatment. Plastic breast surgery was performed at 18 years. Establishing the genotypic sex in patients with primary amenorrhea represents a crucial step knowing that intersex disorders bearing Y chromosomal material have a high risk for gonadoblastoma and germ cell tumors. Key words: gonadoblastoma, gonadal dysgenesis.
INTRODUCTION Gonadoblastoma is a rare tumor that occurs almost exclusively in patients with an underlying gonadal dissorder. It accounts for two thirds of gonadal tumors in women with abnormal gonadal development (1). Gonadoblastoma is a benign tumor occuring in intraabdominally located gonads with pure or mixed gonadal dysgenesys; A Y chromosome is detected in over 90% of cases. A differential diagnosis of patients with intersex disorders bearing Y chromosome material is necessary for exclusion of: male pseudohermaphroditism, complete androgen insensitivity, mixed gonadal dysgenesis 45XO/46XY and some patients with *Correspondence to: Mihai Coculescu, Endocrinology Department, “Carol Davila” University of Medicine and Pharmacy, 34-36 Bd. Aviatorilor, 011863, Bucharest, Romania, Phone/Fax: + 4021 3198718, e-mail:
[email protected] Acta Endocrinologica (Buc), vol. II, no. 2, 227-238, 2006 227
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Turner syndrome and molecular evidence of an Y chromosome. This tumor consists of three types of cells: large germ cells (similar to dysgerminoma and seminoma), small cells (resembling immature Sertoli or granulosa cells) and in two thirds of cases Leydig type cells without Reinke crystals and often contains calcifications (2). Gonadoblastoma have potential risk of malignant transformation as germinal component overgrows the stroma, 30% of them develop into dysgerminoma / seminoma, 10% give rise to other malignant germ cell neoplasms and 10% of germinomas / seminomas have demonstrated metastases at the time the diagnostic is established (3). Most of gonadoblastoma arise in phenotypically females (80%), in the first two decades of life and are billateral in 38,6% of cases (4). The incidence of gonadoblastoma in patients with mixed gonadal dysgenesis 45,XO/46XY, androgen insensitivity and male pseudohermaphroditism is 30-66% and 7-10% in Turner patients with evidence of Y chromosome material (5) or even higher – 33% as reported by others (6).
CASE REPORT Patient DC, aged 15 years presented for primary amenorrhea. Phenotype was female, sex identity – female, height 181 cm, clinical examination and usual laboratory parameters were normal, excluding associated malformations or morbidity. External genitalia had a normal female appearance. Transvaginal ultrasound revealed a small uterus (4 cm long) without endometrial echoes and could not identify the gonads. Vaginoscopy showed a normal 80/23 mm vagina. CT scan was able to identify the right gonad of 18/10 mm in the proximity of iliac bifurcation and the left gonad enlarged, with extrapelvic location. Karyotype and G banding of blood lymphocytes showed a normal 46XY chromosomial constitution. Hormonal assessment established the diagnostic of hypergonadotropic hypogonadism by increased FSH (39.69 mUI/ml) and low testosterone (0.17ng/ml) level. Estradiol level was in the normal male range – 28.07pg/ml and DHEA was increased (21ng/ml). The patient underwent billateral gonadectomy and histologic examination of the gonads established the diagnostic of left gonadoblastoma (Fig. 1) and right teratoma in a dysgenetic gonad. Postoperatory evolution was uneventful. After transdermal estrogens a 3 days spotting ensued. Unopposed estrogen therapy was given for three months and then the patient received transdermal combined therapy and experienced cyclic vaginal bleedings. Secondary female characteristics maintained. At 16 years, radiologic examination revealed still active growth plates. At 18 years, breast plastic surgery was performed (Fig. 2).
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Figure 1. Gonadoblastoma germ cells with abundant clear cytoplasm accompanied by smaller cells of sex-chord type.
DISCUSSION The discordance between phenotypic sex, which was female, and genotypic sex – male (46XY) establishes the diagnostic of XY sex reversal. Male genotypic sex was clinically suggested by the patient’s height of 181 cm at 15 years of age (that could be approximated as near adult height) significantly higher than target height for a girl – 171.5 cm and approaching target height for a boy – 184.5 cm. Target height was calculated from midparental height + 6.5 cm. Wolffian derivatives were lacking (epididymis, vas deferens and seminal vesicles) reflecting
Figure 2. The patient, aged 18, after plastic breast surgery.
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the absence of testosterone action during organogenesis of the male genital tract and the presence of female external genitalia proved the lack of dihydrotestosterone action on the urogenital sinus. Mullerian derivatives (uterus, vagina, fallopian tubes) were present, though hypoplastic, which means the antimullerian hormone (AMH) secreted by Sertoli cells was deficient or AMH receptivity was altered and allowed exclusion of defects in testosterone biosynthesis and action causing XY sex
Figure 3. Genetic control of testis development. 230
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reversal, disorders in which mullerian derivatives are absent (LH/hCG resistance, StAR deficiency, CYP17 deficiency, Smith Lemli Opitz syndrome, 17β hydroxysteroiddehydrogenase type 3 deficiency, complete androgen resistance) and ATRX mutations. Testicular dysgenesis cumulates both deficiencies – AMH and testosterone – and could be suggested by increased FSH, low testosterone, but was not confirmed histologically in the right gonad. Often, because part of gonad is replaced by tumor, a diagnosis of the underlined gonadal abnormality may be impossible (1). In our case, the gonad in which the gonadoblastoma was found is of unknown nature. The right gonad with teratoma seems to be a dysgenetic gonad. It was reported that in some extremely rare cases, an apparently normal ovary was found in patients with gonadoblastoma. Table 1. Mutations in genes involved in testicular development causing XY sex reversal in humans Gene
Locus
Phenotype
SRY WT1
Yp11 11p13
SF1 SOX9
9q33 17q24
XY sex reversal – deletions – WAGR syndrome – Denys Drash syndrome – Frasier syndrome – XY sex reversal associated or not with adrenal insufficiency – campomelic dysplasia
DAX1
Xp21.3
Duplications: XY sex reversal (mutations cause adrenal hypoplasia congenita and hypogonadotropic hypogonadism)
DHH
12q12
DMRT1
9p21-24
– XY sex reversal – Partial testicular dysgenesis and minifascicular neuropathy XY sex reversal, mental retardation craniofacial abnormalities
10q-
10q25-qter
Urogenital anomalies
ATRX
Xq13.3
Thalassemia, mental retardation, genital anomalies (absent mullerian derivatives; in all the other mutations are present)
TSPYL
6q22
Testicular dysgenesis and sudden infant death
Whether endocrine disrupters can generate the gonadal dysgenesis syndrome is still a matter of debate (7); moreover, it would be possible that factors encoded by genes of certain Y chromosome haplogroups may be particularly susceptible to environmental influences that cause testicular dysgenesis syndrome (8). In cases of XX or XY gonadal dysgenesis of undetermined origin gonadal sex chromosomal mosaicism may be the cause (9). It is hypothesized also that numerical and structural aberrations of sex chromosomes are not a prerequisite for the appearance of testicular dysgenesis which is more frequently associated with the 46XY karyotype. The incidence of neoplastic lesions is related more to the severity of testicular organogenesis
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disturbances than it is to aberrations in sex chromosomes, a less disturbed testicular structuralization predisposing to germ cells neoplasms (10). However, testicular dysgenesis is certainly the result of a perturbed testis development which occurs during a relatively narrow time window and it is governed by many genes and transcriptional regulators that act in a spatiotemporal coordinated pattern. The developmental factors known to date may affect DNA bending, modulate chromatin remodelling, form complexes that activate transcription or repress it, specify progenitor cell types and dictate cell fate. Crosstalk among intracellular signalling pathways mediate transcriptional responses (11). Reverse genetic approaches on human sex reversal syndromes and mouse gene knockout studies identified genes encoding transcription factors (SRY, SOX9, DMRT1, GATA4, WT1, LHX9), orphan nuclear receptors (SF1 and DAX1) and cell signalling molecules (AMH, WNT4, FGF9, DHH) that intervene in the sex determination cascade (Fig. 3). Sex determination can be defined as the proliferation, migration and differentiation of supporting cells to become Sertoli cells, committing the fate of the bipotential gonad to the testis pathway (12). The Sertoli cells control differentiation of surrounding cells into Leydig or myoid cells, promote vasculogenesis and mitotic arrest in germ cells. This switch is accomplished by SRY – a key gene located on the short arm of the Y chromosome which activates testis forming genes or represses ovary forming genes, or both. SRY point mutations or deletions are found in only about 15% of XY sex reversed patients; most mutations are “de novo”, but there are cases in which the fertile father of an XY sex reversed individual carries, intriguingly, the same mutation that is probably compensated by other genes and does not occur (12). In table 1 are shown the genes responsible for 46XY sex reversal in humans. SRY expression occurs only in the Sertoli cell lineage and is increased in mice by GATA4 and Fog2 (friend of GATA), Ir (insulin receptor), Irr (insulin related receptor), Igf1r (insulin growth factor 1 receptor) (13). Fgf9 (fibroblast growth factor 9) acting on FgfR2 also stimulates proliferation of preSertoli cells, plays the role of a male specific chemoattractant for immigrant mesonephric cells that will contribute to the structuralization of testes cords as endothelial and peritubular myoid cells and, like SRY, induces SOX9 expression. These genes, when mutated, cause XY sex reversal in mice but mutations were not described in humans (11). SRY transcription is regulated by SF1, WT1 and an ubiquitous transcription factor, Sp1, which cooperates with SF1 (12). WT1 mutations cause Denys Drash syndrome characterised by Wilms tumor, severe renal disease (mesangial sclerosis) and dysgenetic gonads leading to ambigous genitalia in males and Frasier syndrome characterized by lack of +KTS isoforms generating XY sex reversal (complete testicular dysgenesis), predisposition to the development of a gonadoblastoma, late onset glomerulopathy (focal glomerular sclerosis) (14, 15). WT1 mutations are found in patients with isolated genital anomalies only in rare cases and recently a WT1 mutation (P181S) 232
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was described in an XY patient with micropenis, severe hypospadias, cryptorchidism, normal androgen production, androgen resistance, absence of renal disease and coarctation of the aorta (16). WT1 controles kidney and gonad development by specifying coelomic epithelial cells and ensuring their survival. WT1 acts upstream two orphan nuclear receptors – SF1 and DAX1; WT1 and SF1 synergize to enhance transcription of AMH, this interaction being repressed by DAX1 (11). WT1 encodes a transcription factor with four zinc finger motifs as a DNA/RNA binding or protein – protein interaction domain. WT1 binds and acts synergistically with SRY to activate transcription from a promoter containing a SRY binding site. Mutant WT1 is not recruited efficiently to SRY binding sites and results in an impaired testes development (17). WT1 gene can give rise to 24 different isoforms by alternative splicing, alternative translational start sites and RNA editing. There are +KTS and –KTS isoformes distinguished by the presence or absence of three aminoacids – Lys, Thr, Ser (KTS) – between the third and the fourth zinc fingers. The +KTS isoforms act as a transcription factor and the –KTS isoforms are involved in mRNA production and processing and have independent roles in sex determination, WT1 (-KTS) isoforms contributing to the full SRY expression and WT1 (+KTS) being impplied in SRY processing and stability (12). SF1 mutations are rare. There are two known cases of XY sex reversal and adrenal insufficiency (18) and recently two cases of testicular dysgenesis without adrenal insufficiency were described (19, 20) suggesting that the human testis is more sensitive to loss of SF1 function than the adrenal, or the adrenal may have a greater capacity to undergo compensatory growth and function. SF1 gene dosage is of major importance, generating different phenotypes. SF1 codes for an orphan nuclear receptor which acts as a key regulator of gonadal axis and adrenal steroidogenesis; in Sertoli cells regulates AMH and in Leydig cells regulates the expression of steroidogenic enzymes; it is also expressed in the ventromedial hypothalamus and in pituitary gonadotropes. SF1 is necessary for survival of early progenitors of the adrenal and gonad by stimulating cell proliferation and its full expression is conditioned by Lhx9, m33 and Pod1 in mice (11). WT1 and SF1 synergize to increase the expression of genes driven by SF1 and the interaction of SOX9 and SF1 appears to have a role in the greater expression of SF1 in the fetal testis (14). SOX9 mutations in humans cause campomelic dysplasia – a dominant lethal disorder characterized by bowing of the long bones, narrow ilia, cleft palate, absence of olfactory bulbs and tracts, heart and renal malformations, hypoplastic lungs, narrow thorax, delayed bone age and in 75% of 46XY affected individuals – testicular dysgenesis and sex reversal (12). Duplication of SOX9 was described in a SRY negative female to male sex reversed patient suggesting that overexpression of SOX9 can compensate for the lack of SRY (21). SOX9 upregulates expression of AMH by cooperative interaction with SF1. Similarly, WT1 and GATA4 interact with SF1 to upregulate AMH. The 233
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ability of the SOX9 HMG box to bend DNA may bring SF1 and GATA4 in closer proximity to each other and along with WT1 and HSP70 form a tightly associated protein complex that activates AMH transcription (12) SOX9 binds as a dimer in genes involved in chondrocyte differentiation (COL11A2, COL9A2) but binds as a monomer to the regulatory region of SF1; mutations that disrupt dimerization affect chondrogenesis but not sex determination explaining why campomelic dysplasia needs not to be associated to XY sex reversal (22). DAX1 duplications cause testicular dysgenesis with 46XY sex reversal. DAX1 can antagonize the transcriptional activation function of SF1 by recruiting the nuclear corepressor, thus inhibiting SF1 mediated expression of SRY and/or by a direct competition for sites involved in male sex determination (12). SF1 and DAX1 function as transcriptional antagonists for many target genes in vitro but they act independently or cooperatively in vivo in male gonadal development. Though it was thought that mutations of DAX1 permit a normal testicular organogenesis and are characterized only by congenital adrenal hypoplasia and hypogonadotropic hypogonadism, some affected men showed unresponsiveness to gonadotropin treatment (14). In Sf1 deficient mice Cyp17 and Cyp11a1 are reduced in a dose dependent manner but in Sf1/Dax1 double mutants are reduced further indicating that loss of Dax1 does not compensate for reduced Sf1 activity. Moreover Dhh and Amh expression was reduced transiently in single and double mutants but SOX9 was expressed suggesting that various Sertoli cell genes are differentially sensitive to Sf1 and Dax1 (11) Dax1 null mice have gonadal defects in testis cord morphogenesis and peritubular myoid cell proliferation. DHH mutations were reported in three cases with complete testicular dysgenesis (23) and one patient with partial testicular dysgenesis and polyneuropathy (24) proving that localization of mutations influences phenotypic expression. DHH is secreted by Sertoli cells and induces Leydig cells differentiation in a paracrine manner, acting on the receptor Ptc1 (patched 1). Pdgfr α (platelet derived growth factor receptor α) is believed to act upstream of Dhh and it is involved also in mesonephric cells migration and full Cyp11a1 expression. The X linked gene Arx (aristaless) also influences Leydig cell development based on expression of 3βHSD (11). Haploinsufficiency or deletions of DMRT1 result in sex reversal. This gene has a male specific expression in the early stages of gonadal differentiation (genital ridge, developing Sertoli cells). Several human DMRT genes exist and map to three well defined regions on chromosome 1, 9 and 19, one gene on chromosome 19 having an additional homologue on chromosome X. These regions harbor multiple syntenic genes sharing highly specific paralogy relations. The 9p21-24.3 bands represents the ancestral copy (paralogs are genes present in a single genome as a result of gene duplication ) (25). In mice Dmrt1 is expressed in spermatogonia related to a putative role in mitotic or meiotic cell cycle; mutations cause abnormal Sertoli cell morphology, overproliferation and subsequent apoptosis.
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10q terminal deletions are associated with urogenital anomalies (renal hypoplasia, cryptorchidism, micropenis, hypospadias) and, rarely, XY sex reversal but a candidate gene was not yet identified (14). TSPYL mutations (testis specific Y like gene) cause an autosomal recessive syndrome described in Amish population that associates testicular dysgenesis and sudden infant death (26). The insulin signaling pathway is implied in male differentiation and triple mutants mice for Ir, Irr, Igf1r (insulin receptor, insulin related receptor, insulin growth factor 1 receptor) exhibit male to female sex reversal (13). In humans INSL3 (insulin like factor 3) and its receptor LGR8 (leucine rich repeat containing G protein coupled receptor 8) have a role in testicular descent and germ cell function. A pituitary – testicular axis involving LH and INSL3 was postulated (27) and it was found that LGR8 is expressed in male germ cells and binding of INSL3 prevents apoptosis which suggested a paracrine role in germ cell survival (28) but, till now, mutations of INSL3 and LGR8 have been described only in a minority of cases with cryptorchidism. GATA transcription factors are involved in sex determination and differentiation; GATA4 plays an important role in testis development by regulating genes that mediate Mullerian duct regression and the onset of testosterone production; GATA1 is expressed only in Sertoli cells at specific seminiferous tubule stages; GATA1 and GATA4 stimulate inhibin gene promoter constructs; GATA4 and GATA6 activate genes mediating gonadal steroidogenesis (29). Mutations of GATA genes were not yet described in humans with altered testicular organogenesis. Despite the fact that recent research revealed many aspects of testicular differentiation in most cases with 46XY sex reversal etiology remains unknown. Epigenetic factors (DNA methylation), protein misfolding and misrouting may also be involved. Little is also known about the propensity of dysgenetic testes to develop neoplastic lesions. Germ cells in gonadal dysgenesis exhibit a developmental delay and are prone to malignant transformation if they are able to survive in their inappropiate environment (30). In young subjects the number of germ cells is high, but with advancing age decreases progressively. This loss is patchy – some gonadal areas maintain an adequate number of germ cells while in others all cells disappear (31). TSPY is a testis – specific multicopy gene family located in the GBY (gonadoblastoma on Y) critical region of the Y chromosome that is thought to promote gonadoblastoma formation; its X chromosome homologue (TSPX) is widely expressed, subject to X inactivation and is involved in cell cycle regulation (32). TSPY expression is upregulated in germ cells residing in an unfavorable environment (altered Sertoli cell function as a result of testicular dysgenesis generates such an environment) in an attempt to survive and proliferate. The combination of maturation delay, prolonged expression of OCT 3/4 and abundant TSPY expression can provide the surviving germ cell with an important proliferative advantage leading to clonal expansion (31). OCT 3/4 (POU5F1) is a transcription 235
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factor essential for maintainance of totipotency in embryonic stem cells and apoptosis prevention in migratory cells (33). In the testis its expression gradually decreases until 20 weeks of gestation and thereafter persists in a few cells until 3-9 months postpartum when gonocytes finally differentiate into spermatogonia. OCT 3/4 positive cells are located almost exclussively in the central area of the seminiferous tubule. It is suggested that by reaching the basal lamina, early germ cells lose their pluripotency and start to differentiate; if differentiation does not occur and the cell is not removed by an apoptotic or other mechanism, clonal expansion may lead to carcinoma in situ (31). In dysgenetic testes OCT 3/4 is expressed until 14 months of age, thus increasing the risk for malignant transformation. Gonadoblastoma and carcinoma in situ (CIS) express abundantly OCT 3/4 regardless of age (34). By modulating the level of OCT 3/4 expression in vitro in mice embryonic stem cell-derived tumors, the malignant phenotype of the cells was changed, suggesting that OCT 3/4 is of pathogenetic relevance in the development of these tumors (35). Considering these data, it is advisable to perform gonadectomy in XY sex reversed patients in order to prevent neoplastic transformation. In our case gonadoblastoma was already developped at presentation and made the diagnostic more difficult because tumoral hormonal secretion changed both the clinical picture (breast development) and hormonal assessment. Suprinsingly, the estrogen level was in the normal male range but a weak androgen – DHEA was increased (which would suggest a 3βHSD deficiency if the mullerian derivatives were absent). Establishing the etiologic diagnostic would be helpful in order to detect a putative associated morbidity suggested by a certain mutation (for example if a WT1 mutation would be the cause, the patient should be monitored for a late onset glomerulopathy) but is not essential for the patient’s management.
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