1 Department of Obstetrics and Gynecology, 2 Department of Medical Research and 3 Department of Pathology, Mackay Memorial Hospital, and National Yang-Ming University, 92, Section 2, Chung-Shan North Road, Taipei, Taiwan
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Abstract |
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Key words: androgen receptor gene/complete androgen insensitivity syndrome/germ cell tumour/molecular genetics
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Introduction |
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AIS is inherited as a single X-linked recessive disorder. However, the same mutation of the AR gene in different affected 46,XY males can cause variable clinical phenotypes (McPhaul et al., 1992; Tincello et al., 1997
). About 5% of dysgerminomas are associated with 46,XY gonadal dysgenesis, 45,X/46,XY mixed gonadal dysgenesis and AIS (Berek et al., 1996
). Dysgerminomas or gonadoblastomas develop in about 20 to 30% of 46,XY gonadal dysgenesis patients and about 15 to 20% of 45,X/46,XY mixed gonadal dysgenesis patients, in whom the tumours often arise in the first or second decade (Simpson, 1997
). However, the risk of germ cell tumour in CAIS is considerably lower (probably no greater than 5%) and occurs at a later age (after 25 to 30 years of age) than with other male pseudohermaphrodites (Simpson, 1997
). The rarity of this condition and the interest in its genetic origin and malignant transformation prompted this presentation.
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Materials and methods |
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Surgical exploration revealed the presence of a small uterus measuring 5 x 3 x 1.8 cm, bilateral Fallopian tubes, an ovoid shaped right gonad measuring 2 x 1 x 1 cm and a large greyish solid left adnexal mass measuring 12 x 10 x 7 cm (Figure 5A, B). Bilateral gonadectomy was performed. Histology showed dysgerminoma in the right gonad (Figure 6A
) and gonadoblastoma in the left gonad (Figure 6B
). PALP positivity was seen in the tumour cells (Figure 6C
and Figure 6D
). Surgical staging revealed no extension of the disease. The patient was doing well 12 years after operation. There was no evidence of metastasis of the disease and the breasts were checked normal during postoperative follow-up.
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Results |
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Discussion |
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The development of the gonadoblastoma has been associated with a Y chromosome gene, GBY, in dysgenetic gonads (Page, 1987), loss of heterozygosity for a tumour suppressor gene, RB1 (Antonini et al., 1997
), and 9p24 monosomy (McDonald et al., 1997
). Jørgensen et al. (1997) suggested that germ cell tumours associated with gonadoblastoma arise from carcinoma in-situ cells inside the gonadoblastoma nests. The present report concerns the risk of developing germ cell neoplasia among patients with different mutations in the AR gene. The risk of neoplasia is low below 25 to 30 years of age in patients with CAIS, however, our case 2 developed germ cell tumour at the age of 17. This case raises the question of whether a codon 607 mutation in the DNA-binding domain of the AR gene in CAIS is associated with an increased risk of early development of germ cell tumour. Zinc finger motifs in the DNA-binding domain have been demonstrated to be important for positive control of transcription (Schena et al., 1989
). Arg607 and Arg608 have been proved to be partially surface-exposed and located in adjacent areas in the AR DNA-binding domain (Poujol et al., 1997
). These two arginines are involved in proteinprotein interactions and are important for the correct functionality of the AR gene (Poujol et al., 1997
). Arg607Gln and Arg608Lys point mutations in the DNA-binding domain of the AR gene have been associated with male breast cancer (Wooster et al., 1992
; Lobaccaro et al., 1993
; Poujol et al., 1997
). Several point mutations in the hormone-binding domain have also been reported in prostate cancer tissues (McKusick, 1998
). Whether codon 607 mutation in the DNA-binding domain has a potentially worsening effect of early development of germ cell tumour is unknown and deserves further attention. In particular, more work is required to determine if different mutations in the AR gene correlate with the development of germ cell tumour in CAIS.
Our case 2 had a t(3;10) balanced translocation with two breakpoints 3p21 and 10q24 harbouring tumour suppressor genes. Loss of heterozygosity on chromosome 3p has been reported in various cancers, including lung, renal, breast, ovarian, testicular, cervical, and head and neck cancer (Latif et al., 1997). Lothe et al. (1989) suggested that loss of 3p or 11p alleles is associated with testicular cancer tumours. Several genes assigned to 3p21 have been analysed as potential candidates for tumour suppressor genes, i.e. ACY1 (Kok et al., 1997
), CNAI2 (Magovcevic et al., 1992
), CTNNB1 (Kok et al., 1997
), GPX-1 (Moscow et al., 1994
), hMLH1 (Papadopoulos et al., 1994
; Benachenhou et al., 1998
), ITGA4L (Hibi et al., 1994
), NY-LU-12 (Güre et al., 1998
), SEMA III/F (Xiang et al., 1996
), SEMA IV (Roche et al., 1996), SEMA V (Sekido et al., 1996
) and UBE1L (Kok et al., 1995
). Deletions of chromosome 10q have also been described in gliomas, malignant meningeomas, endometrial carcinomas, and melanoma (Petersen et al., 1997
). Various genes on 10q24 have been associated with neoplastic evolution, i.e. FGF-8 (Payson et al., 1996
), HOX11 (Lichty et al., 1995
) and MXI1 (Eagle et al., 1995
). The chromosomal translocation on the segments 2p21 and 10q24 might involve certain tumour suppressor genes and possibly contributed to early tumour formation of our case 2.
To date, at least 200 point mutations of the AR gene have been described and identified in all eight exons of the AR gene, most commonly in the hormone-binding domain and the DNA-binding domain (Quigley et al., 1995; Hiort et al., 1996
). Glu681Lys has been reported in patients with CAIS and Arg607Gln in patients with partial AIS (Hiort et al., 1996
). It has been shown that phenotypic diversity exists in subjects within an affected family with AIS despite the same AR gene mutation (Batch et al., 1993
; Evans et al., 1997
). Therefore, molecular alteration of the AR gene cannot reliably predict the phenotypic presentation of affected patients (Wiener et al., 1997
). In this study, unlike previous reports, our patient 2 with Arg607Gln presented with CAIS and Müllerian duct remnants. The timing for gonadal extirpation in patients with CAIS remains controversial. Traditionally, the testes are left in place after pubertal feminization because the risk of early development of germ cell tumour in CAIS is rare (Simpson, 1997
). But some investigators recommend orchiectomy as soon as CAIS is diagnosed (Shah et al., 1992
; Patterson et al., 1994b
; Wiener et al., 1997
). Testicular carcinoma in situ has been diagnosed in children with AIS (Müller and Skakkebaek, 1984
) and invasive germ cell tumour has been reported in pubertal patients with AIS (Hurt et al., 1989
). In view of the possibility of providing useful information for therapeutic decisions regarding early orchiectomy in infants or young children with high risk AR gene mutations, such as Arg607Gln in this presentation, we suggest regular molecular genetic analysis of the AR gene in 46,XY females with germ cell tumour and AIS.
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Notes |
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References |
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Submitted on April 22, 1998; accepted on November 10, 1998.