Disorders of sexual development in genetic pediatrics: Three different ambiguous genitalia cases report from Hospital para El Niño Poblano, México.

Abstract

Five pediatric patients with three different disorders of sexual development are reported in this study; the first three male patients (16 years, 4 years and 2 months old, respectively) were diagnosed as having diphallia. These 3 patients had real diphallia, well developed penises, urinarious meatus, and both testicles and one of the case, vessel duplication was reported by urology. All the patients have normal cytogenetic analysis, 46XY. The fourth patient was 2 years old, with hyperplasic clitoris, hyperpigmented tissue similar to labia major (large lips) and internal female organs identified as vagina, uterus and both ovaries. A chimera with two different cells lines [46,XX (48%) and 46,XY (52%)] by cytogenetic studies was reported. And the last child was 2 years 8 months old patient with chromosome translocation, between chromosome Y and 7 chromosomes t(7;Y). Hypospadias pene-escrotal, unilateral cryptorchidism, urinary meatus stenosis and malformed scrotum were diagnosed together with vessel duplication.

Full text

International Journal of Genetics and Molecular Biology Vol. 2(10), pp. 207-216, December 2010
Available online at http://www.academicjournals.org/ijgmb
ISSN2006-9863 ©2010 Academic Journals
Full Length Research Paper
Disorders of sexual development in genetic pediatrics:
Three different ambiguous genitalia cases report from
Hospital Para el Nino Poblano, Mexico
Aparicio-Rodríguez J. M.1,9*, Cuellar-López F2, Hurtado-Hernández ML3, Barrientos-Pérez M4,
Reynoso de Mendoza S.5, Vargas-González R.6, Camacho-Gutiérrez S. F.2,
Marroquin-Garcia I.3, Chatelain-Mercado S.7 and Sierra-Pineda F.8
1Department of Genetics, Hospital para el Niño Poblano, México.
2Department of Urology and Pediatric Surgery, Hospital Para el Niño Poblano, México.
3Department of Citogenétics, Hospital Para el Niño Poblano, México.
4Department of Endocrinology, Hospital Para el Niño Poblano, México.
5Department of Neonatology, Hospital Para el Niño Poblano, México.
6Department of Pathology, Hospital Para el Niño Poblano, México.
7Department of Biotechnology, Universidad Autónoma Metropolitana, México.
8Department of Genetics, Hospital de la Mujer S.S.A. Puebla, Mexico
9Department of Estomatology, Benemérita Universidad Autónoma de Puebla México.
Accepted 15 October, 2010
Five pediatric patients with three different disorders of sexual development are reported in this study;
the first three male patients (16 years, 4 years and 2 months old, respectively) were diagnosed as
having diphallia. These 3 patients had real diphallia, well developed penises, urinarious meatus, and
both testicles and one of the case, vessel duplication was reported by urology. All the patients have
normal cytogenetic analysis, 46XY. The fourth patient was 2 years old, with hyperplasic clitoris,
hyperpigmented tissue similar to labia major (large lips) and internal female organs identified as
vagina, uterus and both ovaries. A chimera with two different cells lines [46,XX (48%) and 46,XY (52%)]
by cytogenetic studies was reported. And the last child was 2 years 8 months old patient with
chromosome translocation, between chromosome Y and 7 chromosomes t(7;Y). Hypospadias pene-
escrotal, unilateral cryptorchidism, urinary meatus stenosis and malformed scrotum were diagnosed
together with vessel duplication.
Key words: Ambiguous genitalia, diphallia, hypospadias, cryptorchidism, chromosome translocation and
chimera.
INTRODUCTION
Disorders of sexual development (DSD), formerly termed
intersex conditions, are considered as clinical events and
an early genetic and clinical diagnosis is important in
order to counsel parents on therapeutic options (Allen,
1976; Bernstein, 1981; Hughes et al., 2006, McLaren et
al., 1984; Rosenfield et al., 1980; Walsh and
Migeo,
*Corresponding autor. E-mail: jmapar@prodigy.net.mx.
1978). However, the problem of early gender assignment
has been challenged by the results of clinical and basic
science research, which show that gender identity
development likely begins in the uterus, where the
techniques for surgical genital reconstruction have been
associated to psychological, interfamilial and social
implications of gender assignment (Perez-Palacios et al.,
1975; W atchel and Bare, 1981; Williams, 1981; Wilson
et al., 1986), which in some cases becomes a real
problem for surgical reconstruction. This study focuses
on newborn genetic evaluation and the differential diag-

208 Int. J. Genet. Mol. Biol.
noses in children with DSD, including pediatric patients
with three specific ambiguous genitalia cases: Diphallia,
hypopadias and cryptorchidism, some of them are
associated with chromosome aberrations as chime-rism
and translocation.
The first three patients in this study were diagnosed
with diphallia, or penile duplication (PD), which is a
medical condition where a male infant is born with two
penises (Abdel, 1972; Carlos de la fuente et al., 2004;
Del Vecchyo et al., 1995; Kapoor and Saha, 1987;
Kaufman et al., 1990; Maruyama et al., 1999; Melekos
and Barbalias, 1986; Camacho-Gutierez et al., 2004). It
has been estimated that one out of 5 million live births in
the United States results in a diphallic birth defect
(Abdel, 1972).
When diphallia is present, a different kind of other
congenital anomalies, such as renal, vertebral and
anorectal duplication are observed. There is also a
higher risk of spina bifida. Infants born with PD and its
related conditions have a higher death rate from various
infections associated with their more complex renal or
colorectal systems. It is thought that diphallia occurs in
the fetus between the 23rd and 25th days of gestation
when an injury, chemical stress or malfunctioning
homeobox genes (Thomas, 2005), hamper the proper
functioning of the caudal cell mass of the fetal mesoderm
as the urogenital sinus separates from the genital
tubercle and rectum to form the penis. This rare
condition has been documented in pigs and other
mammals. (Camacho-Gutierez et al., 2004; Villanova
and Raventos, 1954). It is commonly mistaken that all
sharks have this condition, but in reality they have a pair
of "claspers", which serve a reproductive function.
The fourth patient presented a chromosomal Chimera.
The phenotypic spectrum of 46,XX/46,XY chimeric
patients is variable. It ranges from normal male or female
genitalia to different degrees of ambiguous genitalia as in
this study. Chimerism results from the fusion of two
different zygotes in a single embryo (de Grouchy, 1980),
whereas mosaicism results from a mitotic error in a
single zygote.
It was observed by Lillian in 1998, the simultaneous
presence of 46,XX and 46,XY cell lines in 0.24% of
amniotic fluid cell cultures. True cases of chimerism have
been reported (Hunter et al., 1982; Lawce, 1985; Freiberg
et al., 1988; Amor et al., 1999; Yaron et al., 1999;
Pinhas-Hamiel et al., 2002; Simon-Bouy et al., 2003;
Chen et al., 2005). The first case of chimerism was
reported by Gartler in 1962. Since then, very few cases
have been studied using microsatellite markers, in order
to identify the genetic mechanism involved. Here, we
describe a phenotypical normal patient with ambiguous
external genitalia (Figure 7) and a chromosome formula
46,XX/46,XY, chimera (Figure 8).
The fifth and last patient with ambiguous genitalia had
a Y;7 chromosome translocation. The frequency of
Y/autosome translocations in the general population is
not a rare event, approximately 1 in 2000 (Nielsen and
Rasmussen, 1976; Powell, 1984; Gardner and
Sutherland, 1996). Like any other chromosome, the Y
chromosome can be translocated onto an autosome or a
sexual chromosome, either in a balanced or unbalanced
manner. Translocations between the Y and a non-
acrocentric chromosome are not frequent and may
involve any part of the Y chromosome (Smith et al.,
1979), which often leads to an abnormal phenotype and
infertility (Smith et al., 1979; Delobel et al., 1998;
Goodfellow et al., 1985; Vogt et al., 1996; Vogt, 1999;
Viguié et al., 1982). However, it has been reported that in
Y/autosome translocation, the heterochromatic portion of
Yq could be translocated to an acrocentric chromosome,
(Hsu, 1994). These translocations have been observed in
phenotypically normal individuals and reported in
multiple families, indicating that fertility is usually not
affected (Smith et al., 1979; Hsu, 1994; Cohen et al.,
1981; Alitalo et al., 1988).
MATERIAL AND METHODS
Several studies were performed in 5 pediatric patients with ambiguous
genitalia; in all cases, the karyotyping was carried out using blood after
Giemsa Banding (GTG) banding of chromosomes with enzymes and
stains that was performed according to national and international
standard procedures on peripheral blood lymphocytes from all
patients.
Cases 1, 2 and 3
The first three male patients were diagnosed with diphallia: 16 years
(Figures 1A and B), 4 years (Figures 3A and B) and 2 months old
(Figures 5A and B), respectively. All patients were diagnosed with
real diphallia, well developed with urinarious meatus and both testicles.
Subsequently, hormonal studies were performed by endocrinology and
one of the case vessel duplication was observed by urology with pelvic
ultrasounds. As such, all the patients underwent normal cytogenetic
analysis, 46XY (Figures 2, 4 and 6). karyotyping was carried out on
blood after GTG banding. Pathology studies were also performed to
the surgered penises.
Case 4
The fourth pediatric patient in this study was a 2 years old with
ambiguous genitalia (Figure 7), which was also studied by
endocrinology with sexual hormonal studies, urology with pelvic
ultrasound. Genetic and cytogenetic studies reported two different
types [46,XX (48%) and 46,XY (52%)] (Figure 8). It was observed in
the patient karyotyping carried out using blood after GTG banding.
Case 5
The last pediatric patient in this study was a 2 years 8 months old
patient with hypospadias and cryptorchidism (Figures 9 and 10) and
was diagnosed by urology, hormonal studies performed by
endocrinology. By genetic and cytogenetic studies, chromosome
translocation between the sexual Y chromosome and 7 was observed,
t(7;Y) (Figure 11) and was also carried out using blood after GTG.

Aparicio-Rodriguez et al 209
A
B
Figure 1. A. The sixteen years old patient was diagnosed with real diphallia, well developed penises with urinarious
meatus, and both testicles, hormonal studies were performed by endocrinology and vessel duplication was observed by
urology with pelvic ultrasounds. B. The best and well formed penis was left after surgery and his complex renal or
colorectal systems were reconstructed.
Figure 2. The 16 years old patient karyotipe reported normal cytogenetic analysis, 46XY. karyotyping was carried out
on blood after GTG banding.
Pelvic ultrasound studies were performed (Figure 12).
RESULTS AND DISCUSION
Recently, the Lawson Wilkins Pediatric Endocrine
Society, (LWPES, 2008) and the European Society for
Pediatric Endocrinology, (ESPE, 2010) have published
proposed changes to the nomenclature and definitions of
disorders in which the development of chromosomal,
gonadal, or phenotypic sex is atypical (Allen, 1976,
Hughes et al., 2006). They proposed to change the
nomenclature to reflect advances in our understanding of
the pathophysiology of these sexual disorders in order to
the help the affected patients concerned.
Previous terminology and revised nomenclature of
disorders of sexual development (DSD) were based on
new nomenclature: 1.-Sex chromosome DSD
[46,XX/46,XY (chimeric, ovotesticular DSD)], 2.-46,XY
DSD [Disorders of testicular development (complete and
partial gonadal dysgenesis)] and other (severe hypospa-
dias, cryptorchidism). (kaefer et al., 1999; Aarskog, 1971;
Keenan, 1980).
In relation to embryology of sexual differentiation, the
physical sex determination begins with genetic sex,
where chromosomal sex determines gonadal sex. The
type of gonad present determines the differentia-
tion/regression of the internal ducts (that is, müllerian
and wolffian ducts) that determines the phenotypic sex
(Perez-Palacios et al., 1975; Sheehan et al., 1985).

210 Int. J. Genet. Mol. Biol.
A
B
Figure 3. A. The four years old patient was diagnosed with real diphallia, well developed penises with urinarious
meatus and both testicles, hormonal studies were performed by endocrinology. B. The best and well formed penis was
left after surgery and his complex renal or colorectal systems were reconstructed.
Figure 4. The four years old patient karyotipe have normal cytogenetic analysis, 46XY. karyotyping was carried out
on blood after GTG banding.
Gender identity is determined by both phenotypic appea-
rance and the brain's prenatal and postnatal develop-
ment as influenced by the environment. Gonadal
differentiation is determined during the second month of
fetal life. The information present on the short arm of the
Y chromosome called testis-determining factor (TDF) is a
35–kilobase pair (kbp) sequence and there is also an
area termed the sex-determining region of the Y
chromosome (SRY) (Bernstein, 1981; McLaren et al.,
1984; Wilson et al., 1986). When this region is absent or
altered, the indifferent gonad develops into an ovary.
The existence of patients with 46,XX testicular DSD, who
have testicular tissue in the absence of an obvious Y
chromosome or SRY genetic material, requires other
genes that are important to testicular development inclu-
ding other chromosomes: X chromosome (DAX1), 9q33
(SF1), 11p13 (WT1), 17q24-q25 (SOX9), and 19q13.3
(AMH) (Allen, 1976; McLaren et al., 1984; Wilson, 1972).
In ambiguous genitalia, the internal ducts may be altered
when testicular tissue is absent; the fetus
morphologically begins and completes the internal sex
duct development and external phenotypic development
of a female. When testicular tissue is present, two
produced substances appear to be critical for

Aparicio-Rodriguez et al 211
A
B
Figure 5. A. The two months old patient was diagnosed with real diphallia, well developed penises were observed
although a upper protuberance was observed, and was thought to be a pseudotripallia. However by pathological studies
a lipid content tissue was reported. W ith urinarious meatus, and both testicles, hormonal studies were performed by
endocrinology. B. The best and well formed penis was left after surgery and his complex renal or colorectal systems
were reconstructed.
Figure 6. The two months old patient karyotipe have normal cytogenetic analysis, 46XY. karyotyping
was carried out on blood after GTG banding.
development of male internal sex ducts and an external
male phenotype, namely, testosterone and müllerian-
inhibiting substance (MIS) or AMH. The differentiations
of external genitalia of both sexes are identical during the
first 7 weeks of gestation. Without the hormonal action of
the androgens testosterone and dihydrotestosterone
(DHT), (Josso, 1971) external genitalia are psychically
female. In the gonadal male, differentiation toward the
male phenotype actively occurs in the next 8 weeks. This
differentiation is moderated by testosterone, which is
converted to 5-DHT by the action of an enzyme, 5-
alpha Imperato-McGinley et al., 1979; Saenger, 1981)
present within the cytoplasm of cells of the external
genitalia and the urogenital sinus. DHT is bound to
cytosol androgen receptors within the cytoplasm and is
subsequently transported to the nucleus, where it leads
to translation and transcription of genetic material. These
actions lead to normal male external genital
development from primordial parts, forming the scrotum
from the genital swellings, forming the shaft of the penis

212 Int. J. Genet. Mol. Biol.
Figure 7. The two months old patient has hyperplasic clitoris,
hyperpigmented tissue similar as labia majora (large lips) it was
reported by genitography internal females organs were identify as
vagina, uterus and both ovaries.
Figure 8. Karyotipe (50 metaphases) reported a chimera event with
two different cell lines; 24 metaphases (48%); female 46 XX and 26
metaphases (52%); male 46XY was observed by chromosome
studies, carried out on blood after GTG banding.
from the folds, and forming the glands penis from
the tubercle. The state develops from the urogenital
sinus. Incomplete masculinization occurs when testos-
terone fails to convert to DHT. Mixed gonadal digenesis
(MGD) is the second most common cause of DSD.
Hypospadias occurs at a rate of 1 case per 300 live male
births; in less than 1% of patients, hypospadias occurs
with unilateral or bilateral cryptorchidism (Kaefe et al.,
1999; Keenan, 1980). It should be diagnosed as DSD in
patients with both hypospadias and cryptorchidism
Figure 9. The last pediatric patient in this study was a 2 years 8
months old patient with hypospadias pene-escrotal, unilateral
cryptorchidism, urinary meatus stenosis, and malformed scrotum.
Figure 10. The last patient with hypospadias pene-escrotal, unilateral
cryptorchidism, urinary meatus stenosis, and malformed scrotum,
after surgery reconstruction.
(Figures 9 and 10) as in the last patient in this study
with a Y;7 chromosome translocation (Figure 11). It is
thought that diphallia occurs in the fetus between the
23rd and 25th days of gestation when an injury, chemical
stress, or malfunctioning (Abdel, 1972; Carlos de la
fuente et al., 2004; Del Vecchyo et al., 1995; Kapoor
and Saha, 1987; Kaufman et al., 1990; Maruyama et al.,
1999; Melekos and Barbalias, 1986) homeobox genes
hamper proper functioning of the caudal cell mass of the
fetal mesoderm as the urogenital sinus separates from the
genital tubercle and rectum to form the penis (Thomas, 2005).

Figure 11. By genetics and cytogenetic studies chromosome were
performed in the last patient, where translocation between the
sexual Y chromosome and 7 was observed, t(7;Y) it was also
carried out on blood after GTG.
This rare condition has been documented in pigs and
other mammals (Camacho-Gutierez et al., 2004;
Villanova and Raventos, 1954). It is commonly mistaken
that all sharks have this condition, but in reality, they
have a pair of "claspers", which serve a reproductive
function.
The oldest patient was a 16 years old male with a true
difallia (Figure 1, A and B), who was thought to be a
female where both penises were confused to be part of
female external genitalia, a difficult case where a
multidisciplinary medical and psychological team had to
work together with the patient in order to understood the
real chromosomal and psychical sex. However, the sex
orientation of this patient was that of a male, which was
easier for him to accept all physical, surgical, clinical and
psychological changes. Nevertheless, the patient still had
her family, friends and society to affront as a new male
human being. These psychosocial aspects are therefore,
important for modern treatment of patients with ambi-
guous genitalia, which involves a team-oriented
approach as mentioned before. This gender-assignment
team should be as early as possible (new born) as both
younger patients in this study (Figures 3 and 5), and
usually involves neonatologists, geneticists, endocri-
nologists, surgeons, counselors, physiologists and
ethicists (Hollowell, 1977). The goal is to provide appro-
priate medical support and counseling regarding care
and therapy as in the case of the 16 years old patient.
The topic of early gender reassignment is currently under
debate. Moreover, Infants born with penis duplication and
its related conditions have a higher death rate from
various infections associated with their more complex
renal or colorectal systems.
In relation to chimeric patients with a 46,XX/46,XY
karyotype, only a small number have been reported in the
Aparicio-Rodriguez et al 213
literature. In most cases, this condition has
been diagnosed at birth, due to the presence of ambi-
guous external genitalia; however, in this study although
genitals were not well developed (Figure 7), the cytoge-
netic diagnosis was done using two months old baby,
since the family considered the baby as a normal female
patient. According to Danon (1996), these cases account
for about 13% of true hermaphrodites. The phenotype
from these patients varies from normal male or female
external genitalia (Froesch et al., 1983; Freiberg et al.,
1988; Bromilow and Duguid, 1989) to different degrees of
ambiguous genitalia (Fitzgerald et al., 1979; Farag et al.,
1987; Poissonnier et al., 1987; Green et al., 1994; Siou et
al., 1994; Sawai et al., 1994) as the patient in this study
(Figure 7). Infertility in patients with 46,XX/46,XY results
and normal genitalia have been observed in male
patients (Watkins et al., 1981; Schoenle et al., 1983) and
female (Bromilow and Duguid, 1989; Verp et al., 1992).
In relation to the patient in this study with 48% 46,XX and
52% 46,XY from 50 metaphases in the performed
karyotype (Figure 8), genitalia is considered as chimera
rather than mosaic, even though a molecular analysis
has not been provided. A mosaic contains genetically
different cells originating from a single zygote. It results
from a mitotic error during the first blastomeric division or
at a later stage. Niu (2002) reported the first case of
mosaicism proven at the molecular level in a herma-
phrodite individual [46,XX (39)/46,XY (9)]. Chimerism is a
rare condition where cell lines originate from two distinct
zygotes. Chimerism is thought to result from the
fertilization of two oocytes by two sperms and subsequent
fusion of two zygotes into one single embryo. This
condition is called tetragametic chimera, confirmed with
molecular studies by Green et al. (1994), Uehara et al.
(1995), Bonthron (1997) and Strain et al. (1998). In
conclusion, we report in this fourth patient a chimera with
normal physical phenotype and ambiguous genitalia.
However, in the future, polymorphic DNA marker
analysis should be performed to distinguish chimera from
mosaic and to determine the mechanism leading to
46,XX/46,XY chimera.
In the last case in this study, although the incidence of
Y/autosome translocations is low (Nielsen and
Rasmussen, 1976; Powell, 1984; Gardner and Sutherland,
1996), whereas involvement of non-acrocen-tric chromo-
somes often leads to infertility, in this study, all 20
observed metaphases in the last patiente with t(Y;7)
GTG banding showed that the entire Y chromosome was
translocated onto one of the chromosomes 7, The
patient's father had a normal karyotype (46,XY), demon-
strating that this was a de novo (Y;7) translocation
(Figure 11). Our patient had normal development with
normal phenotype. However, ambiguous genitalia was
diagnosed by hypospadias pene-escrotal, unilateral
cryptorchidism, urinary meatus stenosis, and malformed
scrotum that needed urological surgery (Figures 9 and
10). The cytogenetic analysis of GTG banded chromo-

214 Int. J. Genet. Mol. Biol.
Figure 12. The last pediatric patient in this study was a 2 years 8 months old patient with hypospadias and cryptorchidism was
diagnosed by urology with pelvic ultrasound studies.
somes revealed a de novo (Y;7) translocation in all
metaphase cells, where no cell mosaisism was reported
(Figure 11).In the future NOR and FISH studies will be
performed to detect the specific translocation
breakpoints, since the patient was not taken any more by
their parents to the hospital. In the present study, an
abnormal segregation of the (Y;7) was found to be
asociated with external and internal genitalia alteracions
as mentioned before. Such chromosome translocation
might interfiere with normal Y genes specific for sexual
development (Barros et al., 2001; Delobel et al., 1998;
Rappold, 1993; Gabriel-Robez and Rumpler, 1990) and
Y telomere deletion, which might ocurr during the fusion
process with the autosomic chromosome 7. The selection
of female embryos by pre implantation genetic diagnosis
(PGD), which has become the method of choice to
influence the gender of a future patient should be
important. It might be considered at genetic counselling
in this specific Y chromosome aberration.
Finally, in relation to mortality and morbidity, medical
aspects of some other disorders of sexual development
might be cosidered, where patients born with ambiguous
genitalia can represent a true medical and social
emergency; as in the case of adrenogenital
syndrome (CAH), (Amrhein et al., 1977; Bongiovanni,
1962), due to salt-wasting nephropathy that occurs in
75% of infants born with CAH, the most common cause
of ambiguous genitalia, as in the pediatric hospital where
this study was performed in Mexico.
Nevertheless all patients with DSD are multidisciplinary
evaluated by endocrinology, urology, cytogenetics and
genetics. DSD frequency might vary depending on their
etiology, such as difallia, quimerism, or chromosome Y;7
translocation. However, congenital adrenal hyperplasia
CAH is still the most common cause of ambiguous
genitalia in the newborn (Dupont et al., 1977; Frasier et
al., 1975).
The earlier the diagnosis is done, the best of the
physical, sociological and psychological life for the
patient, as the first 16 years old male patient with difallia
in this study, who was thought by his family, friends and
society to be a female patient. Some pediatric patients
with DSD with a normal phenotype, the diagnosis could
be missed. This might be an important issue where earlier

treatment is associated to a better quality of life for the
patient.
ACKNOWLEDGMENTS
The authors would like to thank the Director of the
Hospital Para El Nino Poblano, Dr. Sergio Ivan Assia
Robles and the Director of the Faculty of Estomatology
from the Autonomous University of Puebla, Mtro. Jorge
A. Albicker Rivero, for their incondicional support.
REFERENCES
Aarskog D (1971). Intersex conditions masquerading as simple
hypospadias. Birth Defects Orig. Artic. Ser., 7(6): 122-30.
Abdel A (1972). Diphallia, J. Urol., 108: 357.
Alitalo T, Tiihonen J, Hakola P, la Chapelle A (1988). Molecular
characterization of a Y;15 translocation seggregating in a family. Hum
Genet., 79: 29-35.
Allen TD (1976). Disorders of sexual differentiation. Urology, 7(4): 1-32.
Amrhein JA, Klingensmith GJ, Walsh PC (1977). Partial androgen
insensitivity: the Reifenstein syndrome revisited. N Engl. J. Med.,
297(7): 350-6.
Amor D, Delatycki MB, Susman M, Casey E, Nash T, W arne G, Hutson J
(1999). 46,XX/46,XY at amniocentesis in a fetus with true
hermaphroditism. J. Med. Genet., 36: 866-869.
Barros A, Carvalho F, Fernandes S, Torgal A, Silva J, Sousa M (2001).
Population screening of Y-chromosome microdeletions in Portugal: a
study involving 428 infertile male patients. Hum. Reprod., 16: 189.
Bernstein R (1981). The Y chromosome and primary sexual
differentiation. JAMA, 245(19): 1953-6.
Bongiovanni AM (1962). The adrenogenital syndrome with deficiency of 3
beta-hydroxysteroid dehydrogenase. J. Clin. Invest., 41: 2086-92.
Bonthron DT (1997). Amalgamation of in vitro fertilized embryos, resulting
in birth of a true hermaphrodite chimera. Am. J. Hum. Genet., 61: A147.
Bromilow IM, Duguid JK (1989). The liverpool chimaera. Vox Sang., 57:
147-149.
Carlos de la fuente G (2004). Duplicacion Peneana. Revista Venezolana
de Urología, 50(2): 94-95.
Chen CP, Chern SR, Sheu JC, Lin SP, Hsu CY, Chang TY, Lee CC,
Wang W, Chen HE (2005). Prenatal diagnosis, sonographic findings
and molecular genetic analysis of a 46,XX/46,XY true hermaphrodite
chimera. Prenat Diagn., 25: 502-506
Cohen MM, Frederick RW, Balkin NE, Simpson SJ (1981). The
identification of Y chromosome translocation following distamycin A
treatment. Clin. Genet., 19: 335-342.
Danon M, Friedman SC (1996). Ambiguous genitalia, micropenis,
hypospadias, and cryporchidis. Pediatric Endocrinology: a Clinical
Guide 3rd edn (Marcel Deker, New York), pp. 281-304.
de Grouchy J (1980). Jumeaux Mosaïques Chimères et autres aléas de la
fécondation humaine. (Medsi, Paris).
Del Vecchyo CC (1995). Difalia. Presentación de dos casos y revisión de
la literatura. Cir. Plast., 5(1): 21-25.
Delobel B, Djelati R, Gabriel-Robez O (1998). Y-autosome translocation
and infertility: usefulness of molecular, cytogenetic and meiotic studies.
Hum. Genet., 102: 98-102.
Dupont B, Oberfield SE, Smithwick EM (1977). Close genetic linkage
between HLA and congenital adrenal hyperplasia (21-hydroxylase
deficiency). Lancet, Dec 24-31 ;2.
European Society for Pediatric Endocrinology. ESPE (2010).
www.eurospe.org. www.eurospe.org/clinical/clinical_publications.html
Farag TI, Al-Awadi SA, Tippett P, el-Sayed M, Sundareshan TS, Al-
Othman SA, el-Badramany MH (1987). Unilateral true hermaphrodite
with 46,XX/46,XY dispermic chimerism. J. Med Genet. 24: 784-786.
Fitzgerald PH, Donald RA, Kirk RL (1979). A true hermaphrodite dispermic
Aparicio-Rodriguez et al 215
Niu DM, Pan CC, Lin CY, Hwang B, Chung MY (2002). Mosaic or
chimera with 46,XX and 46,XY karyotypes. Clin. Genet., 15: 89-96.
Frasier SD, Thorneycroft IH, W eiss BA (1975). Letter: Elevated amniotic
fluid concentration of 17 alpha- hydroxyprogesterone in congenital
adrenal hyperplasia. J. Pediatr., 86(2): 310-2.
Freiberg AS, Blumberg B, Lawce H, Mann J (1988). XX/XY chimerism
encountered during prenatal diagnosis. Prenat. Diagn., 8: 423-426.
Froesch P, Schonle E, Froesch ER (1983). A patient with 46 XX/46 XY
chimerism without hermaphroditism. The problem of prepuberal
diagnosis of the Klinefelter's syndrome. Schweiz Med. Wochenschr.,
113: 1065-1067.
Gabriel-Robez O, Rumpler Y (1990). The meiotic pairing behaviour in
human spermatocyte carriers of chromosome abnormalities and their
repercussions on reproductive fitness. II. Robertsonean and reciprocal
translocations. A European study. Ann. Genet., 39: 17-25.
Gardner RJM, Sutherland GR (1996). Chromosome Abnormalities and
Genetic Counseling. Sex chromosome translocations New York, Oxford:
Oxford University Press, pp. 95-114.
Gartler SM, W axman SH, Giblett E (1962). An XX/XY human
hermaphrodite resulting from double fertilization. Proc. Natl. Acad. Sci.
USA, 48: 332-335.
Green AJ, Barton DE, Jenks P, Pearson J, Yates JR (1994). Chimaerism
shown by cytogenetics and DNA polymorphism analysis. J. Med.
Genet., 31: 816-817.
Goodfellow P, Darling S, Wolfe J (1985). The human Y chromosome. J.
Med. Genet., 22: 324-344.
Hollowell JG (1977). Embryologic considerations of diphallus and
associated anormalies, J. Urol., 117: 728.
Hsu LYF (1994). Phenotype/karyotype correlations of Y chromosome
aneuploidy with emphasis on structural aberrations in postnatally
diagnosed cases. Am. J. Med. Genet., 53: 108-140.
Hughes IA, Houk C, Ahmed SF, Lee PA (2006). Consensus statement on
management of intersex disorders. J. Pediatr. Urol. 2(3): 148-62.
Hunter A, Brierley K, Tomkins D (1982). 46,XX/46XY chromosome
complement in amniotic fluid cell culture followed by the birth of a
normal female child. Prenat. Diagn., 2: 127-131.
Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE (1974). Steroid
5alpha-reductase deficiency in man: an inherited form of male
pseudohermaphroditism. Science, 186(4170): 1213-5.
Imperato-McGinley J, Peterson RE, Gautier T, Sturla E (1979). Male
pseudohermaphroditism secondary to 5 alpha-reductase deficiency--a
model for the role of androgens in both the development of the male
phenotype and the evolution of a male gender identity. J. Steroid
Biochem., 11(1B): 637-45.
Josso N (1971). Effect of testosterone and of some of its 17-hydroxylated
metabolites on the mullerian duct of the foetal rat, in organ culture. Rev.
Eur. Etud. Clin. Biol., 16(7): 694-7.
Kaefer M, Diamond D, Hendren WH, Vemulapalli S, Bauer SB, Peters CA
(1999). The incidence of intersexuality in children with cryptorchidism
and hypospadias: stratification based on gonadal palpability and meatal
position. J. Urol., 62(3 Pt 2): 1003-6.
Kapoor R, saha M (1987). Complete duplication of the bladder, urethra, an
external genitalia in a neonate: A case report. J. Urol., 137: 1243.
Kaufman A, Guia R, Davila M, Kaufman A (1990). diphallus whith third
urethra. Urology, 35: 257-260.
Keenan BS (1980). Pseudovaginal perineoscrotal hypospadias: genetic
heterogeneity. Urol. Clin. North Am., 7(2): 393-407.
Lawce H (1985). Prenatal chromosome findigs in a case of XX/XY
chimerism. Karyogram, 11: 93-94.
Lawson Wilkins Pediatric Endocrine Society. LWPES (2008).
http://lwpes.org/. http://www.lwpes.org/professionals/snope/index.cfm.
Lillian YFH (1998). Prenatal diagnosis of chromosomal abnormalities
through amniocentesis. In Aubrey Milunsky (Ed.). Genetic Disorders
and the Fetus. Diagnosis, Prevention and Treatment 4th edn (Johns
Hopkins University Press, Baltimore).
Maruyama K, Takahashi A, Kobayashi T, Hatakeyama S, Matsuo Y (1999).
Diphalia in the VATER assciation. J. Urol., 162: 2144.
Melekos M, Barbalias H (1986). Penile Duplication, Urology, 27: 258-259.
McLaren A, Simpson E, Tomonari K (1984). Male sexual differentiation in
mice lacking H-Y antigen. Nature, 312(5994): 552-5.
Nielsen J, Rasmussen K (1976). Y/autosomal translocations. Clin. Genet.,

216 Int. J. Genet. Mol. Biol.
9: 609-617.
chimera? Revisiting an old hypothesis about the cause of the 46,XY/46,XY
hermaphrodite. J. Pediatr., 140: 6732-735.
Perez-Palacios G, Scaglia H, Kofan S (1975). Inherited deficiency of
gonadotropin receptor in Leydig cells: A new form of male
pseudohermaphroditism. Am. J. Hum. Genet., pp. 27.
Pinhas-Hamiel O, Zalel Y, Smith E, Mazkereth R, Aviram A, Lipitz S,
Achiron R (2002). Prenatal diagnosis of sex differentiation disorders: the
role of fetal ultrasound. J. Clin. Endocrinol. Metab., 87: 4547-4553.
Poissonnier M, Janvier D, Cabrol S, Reviron M, Noel L, Reviron J (1987).
True hermaphroditism in a child with a chimeric XX/XY chromosome, a
double erythrocyte population and an unusual Lewis (a+ b+) phenotype.
J. Genet. Hum., 35: 119-129.
Powell C (1984). Sex chromosomes and sex chromosomes abnormalities.
in Gersen SL, Keagle MB (eds) The Principles of Clinical Cytogenetics
New Jersey, Totowa: Humana Press, pp 229-258.
Rappold G (1993). The pseudoautosomal regions of the human sex
chromosomes. Hum. Genet., 92: 315-324.
Rosenfield RL, Lucky AW , Allen TD (1980). The diagnosis and
management of intersex. Curr. Probl. Pediatr., 10(7): 1-66.
Saenger P (1981). Steroid 5 alpha-reductase deficiency. In: Josso N,
ed. Intersex Child, Pediatric Adolesc. Endocrinol., 156-70.
Sawai T, Yoshimoto M, Kinoshita E, Baba T, Matsumoto T, Tsuji Y,
Fukuda S, Harada N, Niikawa N (1994). Case of 46,XX/47,XY, +21
chimerism in a newborn infant with ambiguous genitalia. Am. J. Med.
Genet. 49: 428-430.
Camacho-Gutierez SF, Olvera-Caballero C, Barrientos-Perez M, Aparicio-
Rodriguez JM (2004). Genitourinary reconstruction in a case of penis
duplication associated to bladder duplication, perineal hypospadias and
bowel sequestration. Rev Mexicana de Urologia. 64: 135-138.
Sheehan SJ, Tobbia IN, Ismail MA (1985). Persistent Mullerian duct
syndrome. Review and report of 3 cases. Br. J. Urol., 57(5): 548-51.
Smith A, Fraser IS, Elliot G (1979). An infertile man with balanced Y;19
translocation. Review of Y;autosome translocations. Ann. Genet., 22:
189-194.
Simon-Bouy B, Plachot M, Mokdad A, Lavaud N, Muti C, Bazin A, Vialard
F, Belaisch-Allart J (2003). Possible human chimera detected prenatally
after in vitro fertilization: a case report. Prenat. Diagn., 23: 935-937.
Schoenle E, Schmid W, Schinzel A, Mahler M, Ritter M, Schenker T,
Metaxas M, Froesch P, Froesch ER (1983). 46,XX/46,XY chimerism in
a phenotypically normal man. Hum. Genet., 64: 86-89.
Siou CG, Brauner R, Lortat-Jacob S, Nivot S, Jaubert F, Fellous M,
Nihoul-Fekete C, Rappaport R (1994). True hermaphroditism: genetic
variants and clinical management. J. Pediatr., 125: 738-744.
Strain L, Dean JC, Hamilton MP, Bonthron DT (1998). A true
hermaphrodite chimera resulting from embryo amalgamation after in
vitro fertilization. N. Engl. J. Med., 338: 166-169.
Thomas RB (2005). Homebox genes internet page.
http://www.biosci.ki.se/groups/tbu/homeo.html.
Uehara S, Nata M, Nagae M, Sagisaka K, Okamura K, Yajima A (1995).
Molecular biologic analyses of tetragametic chimerism in a true
hermaphrodite with 46,XX/46,XY. Fert. Steril., 63: 189-192.
Verp MS, Harrison HH, Ober C, Oliveri D, Amarose AP, Lindgren V,
Talerman A (1992). Chimerism as the etiology of a 46,XX/46,XY fertile
true hermaphrodite. Fert. Steril., 57: 346-349.
Viguié F, Romani F, Dadoune JR (1982). Male infertility in a case of (Y;6)
balanced reciprocal translocation. Hum. Genet. 62: 225-227.
Villanova X, Raventos A (1954). Pseudodiphallia, a rare anomaly, J. Urol.,
71: 338.
Vogt PH, Edelmann A, Kirsch S (1996). Human Y chromosome
azoospermia factors (AZF) mapped to subregions in Yq11. Hum. Mol.
Genet., 5: 933-943.
Vogt PH (1999). Y chromosome and single gene deffects that cause male
infertility. in: Jansen R, Mortimer D (eds) Towards reproductive
certainty: fertility and genetics beyond 1999 Carnforth, UK: Parthenon,
pp. 298-312.
Watkins WM, Yates AD, Greenwell P, Bird GW, Gibson M, Roy TC,
Wingham J, Loeb W (1981). A human dispermic chimaera first
suspected from analyses of the blood group gene-specified
glycosyltransferases. J. Immunogenet., 8: 113-128.
Walsh PC, Migeon CJ (1978). The phenotypic expression of selective
disorders of male sexual differentiation. J. Urol., 119(5): 627-9.
Watchel SS, Bare J (1981). The XX testis. In: Josso N, ed. The Intersex
Child, Pediatric Adolescent Endocrinol., S Karger AG. pp. 116-32.
Wilson JD (1972). Recent studies on the mechanism of action of
testosterone. N. Engl. J. Med., 287(25): 1284-91.
Wilson TA, W achtel SS, Howards S (1986). H-Y intermediate phenotype
in male pseudohermaphroditism. J. Pediatr., 109(5): 815-9.
Williams DI (1981). Masculinizing genitoplasty. In: Josso N, ed. The
Intersex Child, Pediatric and Adolescent Endocrinology. S Karger AG.
pp. 237-46.
Yaron Y, Feldman B, Kramer RL, Kasperski SB, Vo T, Feldman GL,
Johnson MP, Evans MI, Ebrahim SA (1999). Prenatal diagnosis of
46,XY/46,XX mosaicism: a case report. Am. J. Med. Genet., 84: 12-14.