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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1115
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 2 339-343
Copyright © 2008 by The Endocrine Society

CLINICAL CASE SEMINAR

XX Maleness and XX True Hermaphroditism in SRY-Negative Monozygotic Twins: Additional Evidence for a Common Origin

Andréa Trevas Maciel-Guerra, Maricilda Palandi de Mello, Fernanda Boechers Coeli, Marcelo Lima Ribeiro, Márcio Lopes Miranda, Antonia Paula Marques-de-Faria, Maria Tereza Matias Baptista, Suzana Guimarães Moraes and Gil Guerra-Júnior

Grupo Interdisciplinar de Estudos da Determinação e Diferenciação do Sexo, Faculdade de Ciências Médicas, UNICAMP, 13083-970 Campinas, São Paulo, Brasil

Address all correspondence and requests for reprints to: Andréa Trevas Maciel Guerra, M.D., Ph.D., Departamento de Genética Médica, Faculdade de Ciências Médicas, UNICAMP, Caixa Postal 6111, 13083-970 Campinas, São Paulo, Brasil. E-mail: atmg{at}fcm.unicamp.br.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Differentiation of testicular tissue in 46,XX individuals is seen either in XX males, the majority of them with SRY gene, or in individuals, usually SRY(–), with ovotesticular disorder of sex development (OT-DSD). Although they are sporadic cases, there are some reports on familial recurrence, including coexistence of XX maleness and OT-DSD in the same family.

Objective: We report on a case of SRY(–) 46,XX monozygotic twins with genital ambiguity.

Methods: Hormonal evaluation included testosterone, FSH, and LH measurements. SRY gene was investigated by PCR and two-step PCR in peripheral leukocytes and gonadal tissues, respectively. Direct DNA sequencing of the DAX-1 coding sequence was performed. Real-time PCR for SOX9 region on chromosome 17 was obtained.

Results: Both twins had a 46,XX karyotype. Twin A had a 1-cm phallus with chordee, penoscrotal hypospadias, and palpable gonads. Serum levels of FSH (2.34 mIU/ml), LH (8.8 mIU/ml), and testosterone (1.6 ng/ml) were normal, and biopsies revealed bilateral testes. Twin B had a 0.5-cm phallus, perineal hypospadias, no palpable gonad on the right, and a left inguinal hernia. Hormonal evaluation revealed high FSH (8.2 mIU/ml) and LH (15 mIU/ml) and low testosterone (0.12 ng/ml). Upon herniotomy, a right testis (crossed ectopia) and a small left ovotestis were found. SRY gene was absent in both peripheral leukocytes and gonadal tissue samples. Neither DAX-1 mutations nor SOX9 duplication was identified.

Conclusions: This case provides evidence that both XX maleness and XX OT-DSD are different manifestations of the same disorder of gonadal development.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
In 46,XY normal males, SRY (sex-determining region on the Y chromosome) is the key gene, which triggers the expression of a complex gene cascade leading to testicular differentiation (1, 2). However, testicular tissue differentiation can be observed in 46,XX individuals, those with XX maleness or true hermaphroditism, now called ovotesticular disorder of sex development (OT-DSD) (3).

XX males usually have normal male genitalia, small azoospermic testes, and hypergonadotropic hypogonadism (4), and most of them carry the SRY gene due to unequal crossing over between X and Y chromosomes during paternal meiosis (5), whereas those who are SRY(–) usually exhibit genital ambiguity, but complete masculinization in an infertile individual has also been described (6). Generally, individuals with OT-DSD have genital ambiguity combined with both ovarian and testicular tissues in various arrangements (ovary plus testis or either gonad plus an ovotestis or two ovotestes); most 46,XX OT-DSD subjects are SRY(–) (7).

There are some reports on familial recurrence of XX males or OT-DSD and on the coexistence of both conditions in the same family as well (8, 9, 10). We report on a rare case of 46,XX SRY(–) monozygotic twins with genital ambiguity, one of them an XX male and the other an XX OT-DSD.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Laboratory assays

LH, FSH, testosterone, and estradiol were measured by electrochemiluminescence (BM/Hitachi Elecsys 2010; Roche Diagnostics, Boehringer, Mannheim, Germany).

Amplification of SRY gene

Peripheral blood samples were collected from patients and parents. An informed consent was obtained according to our institutional guidelines. Genomic DNA was isolated from whole-blood leukocytes using a proteinase K and phenol/chloroform extraction (11). Primers used to amplify SRY HMG box and SRY whole-coding sequence were described elsewhere (12, 13). A CYP21A2 (21-hydroxylase gene) primer pair, which amplify a fragment expanding from exon 3 to exon 6 (forward, 5'-GGACCTGTCCTTGGGAGAC TAC-3'; reverse, 5'-CCTCAGCTGCATCTC CACGA-3'), was used as internal amplification control. Paraffin-embedded gonadal tissue DNA was obtained by treating 25 mg of each sample with 1200 µl of xylene (Synth Chemical Co., São Paulo, Brazil). Samples were vigorously vortexed and centrifuged for 5 min at 3000 rpm at room temperature. To remove residual xylene, samples were treated twice with 1200 µl 100% ethanol (Merck Chemical, Darmstadt, Germany). Room temperature centrifugation at 3000 rpm for 5 min was used to remove supernatant after each treatment. Samples were incubated 10 min at 37 C to eliminate residual ethanol. To extract DNA from gonadal tissue, the DNeasy Blood and Tissue kit (QIAGEN, Hilden, Germany) was used, according to the manufacturer’s instructions. A two-step PCR was performed for SRY HMG box and for an exon 3 to intron 4 CYP21A2 401-bp amplifying fragment (intron 4 reverse primer, 5'-CAGTTCAGGACAAGGAGAGGC-3'). For the first step, a 25-µl final volume PCR was carried out with PCR Master Mix Kit (Promega, Madison, WI) following the provider’s protocol. A second step PCR with the same primer pairs was performed as in the first step, except using 4 µl of the first PCR product as template.

Genotyping

Genotyping was performed by testing three different single-nucleotide polymorphisms (SNPs) in CYP21A2 gene and Taq I restriction fragment length polymorphisms in both C4B and class II HLA genes.

DAX-1 and SOX9 gene analyses

Primers used to amplify the two exons and exon-intron boundaries of the DAX-1 gene were published elsewhere (14). Direct sequencing was performed using the ABI PRISM BigDye Terminator Cycle Sequencing Kit V3.1 Ready Reaction (Applied Biosystems, Foster City, CA) on a 3700 automated sequencer (Applied Biosystems).

Quantitative PCR for SOX9 gene was performed using primers described by Rajender et al. (15). Reactions were carried out in a 7300 Real-Time PCR System (Applied Biosystems), and threshold cycle numbers were determined using RQ Study Software (Applied Biosystems). Reactions were performed in triplicate, and threshold cycle numbers were averaged. The 50-µl reaction mixture was prepared as follows: 25 µl Platinum SYBR Green qPCR SuperMix-UDG (Invitrogen Life Technologies, Alameda, CA), 10 µM of each primer, and different DNA amounts. Normal fertile 46,XY male DNA was used as a standard for real-time PCR assay. Three reactions were set up independently for each concentration of genomic DNA (1.25, 2.5, 5.0, and 10 ng) for drawing the standard plot. Similarly, three independent reactions were set up for each of the two concentrations of the test samples (2.5 and 5.0 ng). The reaction was cycled with preliminary UDG treatment for 2 min at 50 C and a denaturation step for 2 min at 95 C, followed by 45 cycles of denaturation at 95 C for 15 sec, annealing for 15 sec, and primer extension at 72 C for 15 sec. This was followed by melting-point analysis of the double-stranded amplicons consisting of 40 cycles of 1 C decrement (15 sec each) beginning at 95 C. The first derivative of this plot, dF/dT, is the rate of change of fluorescence in the reaction, and a significant change in fluorescence accompanies the melting curve of the double-stranded PCR products. A plot of –dF/dT vs. temperature displays these changes as distinct peaks.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Case reports

The twins were born by cesarean section in the 35th week of gestation due to fetal distress. Pregnancy was complicated by diabetes, depression, and polytrauma in the first month; the mother took metformin, amitriptilin, clonazepam, and fluoxetin and had many radiographs in the first trimester. She had two previous gestations: a 13-yr-old boy from her first marriage and a 9-yr-old boy. Family history was unremarkable except for a maternal aunt with primary amenorrhea.

Twin A had a birth weight of 1530 g, length 40 cm, head circumference 30 cm; 1-min and 5-min Apgar scores were 7 and 8. The child had a 1-cm phallus with chordee and penoscrotal hypospadias, and gonads were palpable bilaterally in the scrotal folds (Fig. 1Go, A and B). Hormonal evaluation at the age of 23 d revealed normal FSH (2.34 mIU/ml), LH (8.8 mIU/ml), and testosterone (1.6 ng/ml) levels, and biopsies carried out at the age of 1 month revealed bilateral testes (Fig. 2Go, A and B).


Figure 1
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  		FIG. 1. External genitalia of twin A (A and B) and twin B (C and D).

 

Figure 2
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  		FIG. 2. Histology of the gonads of twin A (A and B) and twin B (C and D). The sections were stained with hematoxylin and eosin. B is a higher magnification of the boxed area in A and shows immature solid tubules of the prepuberal testis (arrows). D is a higher magnification of the left gonad boxed area in C and shows a primordial follicle (arrow) in ovarian stroma. Note in C the primordial epididymis (asterisk). Magnification, x50 (A and C) and x750 (B and D).

 
Twin B had a birth weight of 1210 g, length 37 cm, head circumference 29.5 cm; 1-min and 5-min Apgar scores were 6 and 8. The child had a 0.5-cm phallus, perineal hypospadias, no palpable gonad on the right, and a left inguinal hernia (Fig. 1Go, C and D). Hormonal evaluation at the age of 23 d revealed high FSH (8.2 mIU/ml) and LH (15 mIU/ml) and low testosterone (0.12 ng/ml). At the age of 1 month, herniotomy revealed the presence of two gonads: the right testis (crossed ectopia) and a small left gonad, which was removed together with an epididymis and Müllerian remnants. This gonad was found to be an ovotestis, with ovarian follicles interspersed among seminiferous tubules (Fig. 2Go, C and D). The right testis was translocated from the left to the right side and orchidopexy was carried out.

Both twins had a 46,XX karyotype (Fig. 3Go, A and B).


Figure 3
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  		FIG. 3. Karyotype of twin A (A) and B (B); arrows indicate the X chromosomes.

 
Molecular studies

SRY gene was negative in peripheral blood leukocytes as verified by PCR using two different primer pairs, one for SRY HMG box (Fig. 4aGo) and the other for the whole coding sequence (data not shown). The CYP21A2 internal amplification control producing a 707-bp fragment was positive in all samples (Fig. 4AGo). To test the presence or absence of SRY in gonadal tissues, a two-step PCR was performed. Negative results were obtained in both steps for twin A and twin B (Fig. 4BGo). To avoid misinterpretation of negative results due to nonamplifying samples, a separated PCR producing an SRY size-equivalent fragment was carried out using a CYP21A2 primer pair and gonadal DNA as template (Fig. 4CGo). Positive results for the 401-kb CYP21A2 fragment led us to conclude that both twins are SRY negative in gonadal tissues as well. Homozygosity between twins was verified after testing three different SNPs in CYP21A2 gene and Taq I restriction fragment length polymorphisms in both C4B and class II HLA genes (data not shown).


Figure 4
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  		FIG. 4. Gel electrophoresis of the PCR amplicons of the SRY and CYP21A2 genes. A, Leukocyte DNA. The SRY HMG region produces a 360-bp fragment, and the CYP21A2 gene, used as internal control, produces a 707-bp fragment expanding from exon 3 to exon 6. L, 1-kb ladder plus (Invitrogen); lane 1, twin A, XX male; lane 2, twin B, XX OT-DSD; lane 3, 46,XX normal female; lane 4, 46,XY normal male; lane 5, blank control (without DNA). B and C, Paraffin-embedded gonadal tissue DNA used as template for the first-step PCR (upper panels) in the two-step PCR procedure; lower panels are the results of the second-step PCR for SRY HMG box (B) and exon 3/intron 4 CYP21A2 fragment (C): lane 1, XX male, right gonad; lane 2, XX male, left gonad; lane 3, XX OT-DSD, gubernaculum; lane 4, XX OT-DSD, right gonad; lane 5, XX OT-DSD, left gonad; lane 6, 46,XX normal female; lane 7, 46,XY normal male; lane 8, blank control (without DNA).

 
No mutations were identified in DAX1 coding sequence. The analysis revealed only heterozygosity for two SNPs (SNP ID rs6150C->T and SNP ID rs2269345G->A) in both children.

The copy number of SOX9 gene in the patients was investigated by real-time PCR assay. There was no evidence for a SOX9 dosage effect because both twins presented an amplification pattern similar to the normal male control (Fig. 5Go).


Figure 5
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  		FIG. 5. Standard curve plot for real-time PCR assay to estimate SOX9 gene copy number. Ct represents the number of the PCR cycle to achieve the threshold fluorescence in the real-time PCR. Reactions were performed in triplicate, and threshold cycle numbers were averaged. Genomic DNA amounts for drawing the standard plot were 1.25, 2.5, 5.0, and 10 ng. Standard plot was constructed with a normal male DNA sample. The test DNA samples were set up with 2.5 and 5.0 ng each for twin A (XX male) and twin B (XX OT-DSD).

 
After discussions with the parents, twin A, an XX male, was assigned a male gender, and twin B, with OT-DSD, a female gender. When the twins were 5 months old, the boy underwent chordee correction and urethroplasty, whereas his sister underwent clitoroplasty, introitoplasty, and right gonadectomy.

When the children were 17 months old, a human menopausal gonadotropin stimulation test was performed (three im injections of Pergonal, 150 IU of FSH and LH on successive days). Testosterone levels increased in twin A (from 0.54 to 1.14 ng/ml) but not in twin B (<0.02 ng/ml both before and after the injections), and there was no response of estradiol in both children (from 13.1 to 12.65 pg/ml in twin A and from 12.53 to 11.76 pg/ml in twin B), indicating absence of gonadal remnants in twin B and reinforcing the diagnosis of XX maleness in twin A.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, we report a case of 46,XX monozygotic twins with genital ambiguity. One is XX male and the other XX OT-DSD. SRY gene is absent in both peripheral leukocytes and gonadal tissues. The possibility of inhibition in the PCR using blood DNA samples was excluded because positive amplification was observed with an internal PCR control gene and for DAX1 and SOX9 genes as well. Similarly, an SRY gene mosaicism in the gonadal tissue was also discarded, because positive amplification was observed for the control gene in the second-step PCR (Fig. 4CGo), whereas SRY-negative results were obtained after both PCR steps for twin A and B (Fig. 4BGo). Hidden SRY mosaicism in gonads is rare and has been described in only two cases of XX OT-DSD (16, 17) and one case of XX maleness (18).

DAX1 and SOX9 have been proposed to function downstream to the SRY gene in the male sex-determination pathway (19, 20).

Originally, DAX1 duplication, an X-linked gene within the DSS locus (dosage-sensitive sex reversal) at Xp21, was considered to cause male-to-female sex reversal in SRY(+) 46,XY individuals (21), whereas mutations in DAX1 coding sequence were associated with hypogonadotropic hypogonadism and congenital adrenal hypoplasia in 46,XY individuals (22). Lately, a function as an early mediator of testes development downstream to SRY has been proposed (19). Sequence analysis of the coding regions of DAX1 in the present cases did not show any mutation.

The human SOX9 gene belongs to the SRY-related HMG box (SOX) gene family and maps to chromosome 17q24. In general, mutations in the SOX9 gene are responsible for Campomelic dysplasia in which skeletal malformations are associated with XY male-to-female sex reversal (23).

Because increased expression of SOX9 has been considered to cause female-to-male sex reversal in 46,XX SRY(–) individuals (24, 25, 26), we investigated SOX9 gene duplications in both children. The results showed normal gene dosage, excluding the involvement of SOX9 in the phenotypes described here.

Either XX male or OT-DSD condition is sporadic in the majority of cases. However, both may coexist within a same family (8, 9, 10). Although SRY(+) sibs with either XX maleness or 46,XX OT-DSD have been described (9), most familial cases are SRY(–), and sibs with SRY(–) XX maleness have been reported (8). Some pedigrees indicate an autosomal recessive inheritance, whereas others suggest an autosomal dominant pattern with incomplete penetrance or even an X-linked mutation transmitted through a carrier 46,XY male (10).

The case presented here is, to the best of our knowledge, the first report on the coexistence of XX maleness and OT-DSD in identical twins, and this finding brings additional evidence that they are different manifestations of the same gonadal development disorder. More reports on twins will be necessary to evaluate the extent to which this trait is inherited, that is, to estimate the heritability of this disorder.

In addition, the many gestational problems referred in the present case suggest that adverse environmental conditions may play a role in testicular differentiation in susceptible SRY(–) 46,XX subjects.

In fact, as pointed out by Mittwoch (27), the idea of a single Y-chromosomal gene responsible for initiating testis differentiation is giving way to the recognition that this gene, in collaboration with non-Y-chromosomal genes, increases proliferation in the cells in which it is active, thus suggesting that the genes required for male sex differentiation act as promoters of growth (28). Hence, these genes must be assumed to interact to some extent with environmental factors (27).


   Footnotes
 
Disclosure Statement: All authors have nothing to disclose.

First Published Online December 4, 2007

Abbreviations: OT-DSD, Ovotesticular disorder of sex development; SNP, single nucleotide polymorphism.

Received May 21, 2007.

Accepted November 27, 2007.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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