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31
Case Report
A CURIOUS CASE OF A 46,XX MALE:
AN UNUSUAL CAUSE OF PRIMARY
HYPOGONADISM
Oren Steen,1 Elizabeth McCready,2 John Booth1
Division of Endocrinology and Metabolism, McMaster University,
1280 Main Street West, Hamilton, Ontario, L8S 4L8, Canada.
1
Department of Pathology and Molecular Medicine,
McMaster University, 1280 Main Street West,
2 Author for Correspondence:
Oren Steen
Email: [email protected]
Conflict of Interest:
The authors have no conflicts of interest to disclose.
Hamilton, Ontario, L8S 4L8, Canada.
ABSTRACT:
Background: 46,XX testicular disorder of sexual development is a rare cause of primary hypogonadism,
characterized by a male phenotype despite a female (i.e. 46,XX) karyotype. In the vast majority of cases, it is caused
by a translocation of Y chromosomal material (containing the SRY gene) onto an X chromosome.
Case presentation: A 38 year-old male was referred to the endocrinology clinic for hypogonadism. His symptoms
included decreased energy, diminished libido, weight gain and gynecomastia. There was no history of testicular
torsion or trauma, cryptorchidism, orchitis, chemotherapy or radiation therapy. Despite 3 years of unprotected
intercourse, his partner had not conceived. Physical examination was significant for bilateral gynecomastia, reduced
androgen-dependent hair growth, and small, soft testes. Laboratory investigations revealed evidence of primary
hypogonadism (low testosterone and elevated gonadotropins). Cytogenetic analysis revealed a 46,XX karyotype with
an SRY translocation onto the short arm of the X chromosome.
Conclusion: We present a rare case of 46,XX testicular disorder of sexual development, a consequence of
translocation of the SRY gene onto an X chromosome. We will review its epidemiology, pathogenesis, presentation,
diagnosis and management.
P
INTRODUCTION:
rimary hypogonadism in males involves an intrinsic
abnormality in the testes. It presents with low serum
testosterone and elevated gonadotropins (follicle
stimulating hormone (FSH) and luteinizing hormone
(LH)). In contrast, central hypogonadism involves
impaired pituitary (secondary hypogonadism) or hypothalamic
function (tertiary hypogonadism), resulting in low serum testosterone
and low or inappropriately normal gonadotropins. Consequences of
hypogonadism depend on its age of onset, but may include ambiguous
or female genitalia if established in the first trimester of gestation;
absence or arrest of pubertal development if occurring at pubertal age;
or loss of libido, erectile dysfunction, gynecomastia, decreased muscle
and bone mass, fatigue and loss of body hair if established during
adulthood.1 Common etiologies of primary hypogonadism include
Klinefelter syndrome, bilateral torsion, orchitis, orchidectomy, and
testicular trauma (induced by surgery, radiation or chemotherapy).2
We report a rare case of a 46,XX testicular disorder of sexual
development (DSD): a phenotypic male with a female karyotype.
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Case Report
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McMASTER UNIVERSITY MEDICAL JOURNAL
CASE PRESENTATION:
A 38-year-old Caucasian male was seen in the endocrinology clinic
for hypogonadism. He presented with a 6 month history of decreased
energy, diminished libido, 18 kg weight gain and gynecomastia. No
changes in his voice or frequency of shaving were noted, although
he mentioned that he only shaved once or twice weekly. He denied
any history of mumps or other testicular infections, testicular trauma,
torsion or cryptorchidism. He had never received chemotherapy or
radiotherapy. His puberty was timely but incomplete: He exhibited
scarce facial hair, as well as decreased hair growth on his arms, legs,
axillae and abdomen. He had normal (i.e. Tanner Stage 5) public
hair. His voice remained midpubertal in pitch. His muscle bulk did
not increase with exercise. Despite 3 years of unprotected intercourse,
his partner had not conceived. He had social difficulties during his
youth and was never particularly athletic. In an effort to alleviate his
hypogonadal symptoms, he had been started on oral testosterone
undecanoate several weeks before his referral with limited effect.
His past medical history was significant for a motor vehicle collision
resulting in a dashboard injury to his knees, a right scapholunate
ligament repair, dyslipidemia and GERD. His medications included
simvastatin, esomeprazole and testosterone undecanoate capsules.
He was divorced, though newly engaged to a different partner, and
worked as a carpenter. He quit smoking three years prior, consumed
one to two alcoholic beverages per week, and denied illicit drug
use. Family history was significant for type 2 diabetes and “heart
problems” in his father.
Figure 1. G
-banded karyotype of the patient demonstrating a
female karyotype, with two X chromosomes and the
absence of a Y chromosome.
On examination, he weighed 117 kg. His blood pressure was 126/92
mmHg and his heart rate was 76 bpm. Respiratory and cardiac
examinations were within normal limits. He had Tanner stage III
gynecomastia bilaterally with palpable glandular tissue. Abdominal
examination was remarkable for a reduced amount of hair growth.
His testicles were soft, measuring 6 mL on the right and 8 mL on the
left (normal range 15-20 mL). No varicoceles were detected.
Laboratory investigations revealed a total testosterone level of 2.0
nmol/L (normal range 7.6-31.4 nmol/L), LH 29 IU/L (normal range
2-9 IU/L) and FSH 45 IU/L (normal range 2-12 IU/L). Prolactin
and iron studies were normal.
A karyotype was requested to assess the possibility of Klinefelter
syndrome. The chromosomal analysis using G-banding (550 bands of
resolution) revealed a 46,XX karyotype (Figure 1). Polymerase chain
reaction (PCR) analysis showed amplification of the SRY locus, a gene
on the Y-chromosome (p11.31). Fluorescence in situ hybridization
(FISH) analysis confirmed translocation of the implicated SRY
gene to the short arm of the X chromosome (Figure 2). A follow-up
appointment was arranged with the genetic counseling service.
DISCUSSION
Our patient had 46,XX testicular DSD, which is a rare cause of
primary hypogonadism. The differential diagnosis for primary
hypogonadism is quite broad, and is listed in Table 1.
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Figure 2. F
ISH analysis. Metaphase FISH using a FISH probe for
the X chromosome centromere (green) and the SRY
locus (red). The SRY probe hybridized to the distal
end of the short arm of one X chromosome homolog
suggesting the presence of Y chromosomal material on
one copy of the X chromosome.
33
PRIMARY HYPOGONADISM IN 46,XX MALE
Table 1. Causes of primary hypogonadism in males.
FETAL ONSET
1. Whole gonadal dysfunction
Gonadal dysgenesis:
Chromosome defects: Deletions of Yp, 9p, XX/XY, XY/X,
other mosaicisms
Gene mutations: SRY, CBX2, MAMLD1, SF1, WT1,
SOX9, DHH, XH2, DHCR, TSPYL1, etc.
Vanishing testes
Klinefelter syndrome
46,XX disorder of sexual development
Ovotesticular DSD
XX males
2. Dissociated gonadal dysfunction
Leydig cells
Hypoplasia/aplasia: LH/CG-R mutation
Steroidogenic defects: CYP11A1, CYP17A1, HSD3B2,
POR, CYB5A, or HSD17B3 mutation
INSL3 mutations
Sertoli cells
FSH receptor mutation
AMH mutation
POST-NATAL ONSET
1. Whole gonadal dysfunction
Prader-Willi syndrome*
X-linked adrenal hypoplasia congenita*
Cranial radiotherapy and chemotherapy*
Lead intoxication*
Marijuana consumption*
Total body irradiation*
Orchitis
Testicular torsion or trauma
Down syndrome
Varicocele
Chronic illnesses: e.g. granulomatous diseases,
amyloidosis, cystic fibrosis, chronic pulmonary disease,
renal failure, neurologic disorders
Late-onset hypogonadism
2. Dissociated gonadal dysfunction
Y chromosome deletions and microdeletions: AZF
Gene mutations: CILD1, USP9Y, etc.
Chemotherapy
Abdominopelvic radiotherapy
Pharmacological treatments: spironolactone, ketoconazole
* indicates combined central and primary hypogonadism
Adapted from (1) with permission.
EPIDEMIOLOGY
46,XX testicular (DSD, formerly known as “XX male syndrome”,
was initially described by Albert de la Chapelle and colleagues in
1964.3 It is a rare disorder with an incidence of 1 in 20,000-25,000
male newborns.4-8 80-90% of cases are SRY (sex-determining region
Y)-positive; 10-20% are SRY-negative.4-6
PATHOGENESIS
During paternal meiosis, “crossing over”, or genetic recombination
of chromosomal material, takes place between the X and Y
chromosomes at homologous sequences of nucleotides known as
pseudoautosomal regions.4 Certain regions of the Y chromosome
– known as sex-determining regions – do not normally participate
in recombination.9 One such region includes the SRY gene (located
on Yp11.3), which plays a pivotal role in the development of the
embryonic testes, and hence male sex determination.4,5,10 As a
consequence of erroneous recombination involving the SRY gene,
patients with 46,XX DSD ultimately have a male phenotype despite
possessing a female (i.e. 46,XX) karyotype. Translocation of the SRY
gene to the X chromosome is almost always a de novo translocation,
although rarely it may be inherited.11 Other rare possibilities include
a de novo or inherited translocation of SRY to an autosome.11
Consistent with their male phenotype, these patients exhibit male
psychosexual identification.12 Infertility is caused by the absence of
the spermatogenesis locus on the long arm of the Y chromosome,
which contains three AZF (azoospermia factor) regions.6,9
SRY-negative 46,XX DSD includes patients with ovotesticular-DSD
(true hermaphrodites having both testicular and ovarian tissue in the
gonads) and testicular-DSD (both gonads are testes with no evidence
of ovarian tissue).6 Their phenotype may result from excessive or
absent actions of other important genetic factors within the sexual
differentiation cascade, including SOX9, DAX-1, Ad4BP/SF-1,
WT1 and GATA4.5,10, Unlike their SRY-positive counterparts, SRYnegative 46,XX DSD patients often present with ambiguous genitalia
at birth with a high incidence of penoscrotal hypospadias and
cryptorchidism, and almost invariably develop gynecomastia around
the time of puberty.6,11 True hermaphrodites may have a uterus or
hemi-uterus, as well as female-range estrogen levels.11
CLINICAL PRESENTATION
Patients present with primary hypogonadism manifesting as small
testes (microorchidism), gynecomastia, non-obstructive azoospermia
and infertility.4,5,8 Penile size is normal, and Müllerian structures are
absent.11 Testes are generally soft, but may become firmer with age.11
Furthermore, these patients may display poor facial hair growth and
female pubic hair distribution.6,8 One notable difference between
46,XX testicular DSD and Klinefelter syndrome is that shorter-thanaverage stature is often seen in the former, which may be related to
the absence of specific growth-related genes on the Y chromosome.5,8
In addition, there is no association between learning disorders
or behavioural issues and 46,XX testicular DSD.11 Although not
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McMASTER UNIVERSITY MEDICAL JOURNAL
warranted for diagnosis, testicular biopsy generally demonstrates
a decrease in size and number of seminiferous tubules, peritubular
fibrosis, absence of germ cells, and Leydig cell hyperplasia.13
In 46,XX testicular DSD, testosterone levels are normal during
puberty but they begin to decline during adulthood leading to primary
hypogonadism.4 Diagnosis in adulthood during investigations for
infertility is a classic occurrence.4-6 46,XX karyotypic abnormalities
have been reported with an incidence of 0.9% in azoospermic males.14
DIAGNOSIS
Diagnosis of 46,XX testicular DSD requires cytogenetic analysis,
which reveals a normal female (46,XX) karyotype. Next, FISH of an
SRY probe to metaphase chromosomes should be undertaken, in order
to determine the nature of the rearrangement.11This may involve SRY
translocated on an X chromosome (most common scenario), or rarely,
SRY translocated on an autosome.11 It is important to determine
the nature of the rearrangement, as the modes of inheritance and
implications for genetic counseling are different.11 Although PCR for
SRY is more sensitive than FISH, it cannot establish the nature of the
chromosomal rearrangement, and hence the inheritance pattern.11
MANAGEMENT
With respect to management of 46,XX testicular DSD, patients
may benefit from psychological support, particularly after disclosing
their diagnosis.11 They require lifelong endocrinology follow-up with
regular bone mineral density (BMD) measurements and treatment
of osteopenia, as well as testosterone supplementation.5 The latter is
generally initiated after age 14 at low doses, and gradually increased
to reach adult levels.11 Our patient had a suboptimal response to oral
testosterone undecanoate, conceivably because the latter is known
to have unreliable oral bioavailability, fluctuating serum levels and
a short half-life, necessitating multiple daily dosing.15 For these
reasons, intramuscular and transdermal testosterone preparations are
preferable. Gynecomastia, if still a concern following testosterone
replacement therapy, can be treated by reduction mammoplasty.11
The only available fertility option short of adoption involves artificial
insemination via donor sperm.5, with success rates on the order
of 14% per cycle and 77% after 12 cycles.16 Genetic counseling
would also be beneficial in order to educate patients on the nature,
inheritance and implications of their condition.11
CONCLUSION
We report a rare case of 46, XX testicular DSD with an SRY
translocation on the short arm of an X chromosome. Cytogenetic
analysis is a crucial investigative tool for this particular condition.
These patients benefit from genetic counseling and lifelong
endocrinology follow-up.
Abbreviations
FSH: follicle-stimulating hormone; LH: luteinizing hormone;
G-banding: Giemsa banding; PCR: polymerase chain reaction; SRY:
sex determining region Y; FISH: fluorescence in situ hybridization;
DSD: disorder of sexual development; AZF: azoospermia factor.
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