An offbeat presentation of primary male infertility: de la Chapelle syndrome

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Case Report
An offbeat presentation of primary male infertility:
de la Chapelle syndrome
Aatish Saraswat
a
, N. Nagaraja
b
, Barun Kumar Chakrabarty
c,*
,
Paresh Singhal
c
a
Resident, Department of Pathology, Armed Forces Medical College, Pune, India
b
Professor (Obstetrics &Gynecology), Command Hospital (Southern Command), Pune, India
c
Associate Professor, Department of Pathology, Armed Forces Medical College, Pune, India
article info
Article history:
Received 26 June 2023
Accepted 10 August 2023
Available online xxx
Keywords:
Disorder of sex differentiation
Primary male infertility
de la Chapelle syndrome
46, XX male
abstract
In 20-30% cases of infertility, a primary defect is found in the male partner and contribute
to 50% of patients overall. Studies have shown that the prevalence of both numerical and
structural chromosomal abnormalities is increased in such men. A few genes have been
implicated in sex development during gonadal and functional differentiation, where the
maintenance of the somatic sex as either male or female is achieved by the suppression of
the alternate route. One such entity in the vast group of male infertility etiologies is the de
la Chapelle syndrome or 46, XX testicular disorder of sex differentiation (DSD), which is a
rare disorder characterized by discordance between the male phenotype and the female
karyotype. This syndrome's exact molecular and genetic basis is yet to be described in full
potential. Due to the rare diagnosis of such cases, we report this case of infertile male
diagnosed as SRY-positive 46, XX testicular DSD, aiming to add to the previously reported
cases in the literature.
©2023 Director General, Armed Forces Medical Services. Published by Elsevier, a division of
RELX India Pvt. Ltd. All rights reserved.
Introduction
46, XX testicular disorder of sex differentiation (DSD), or de la
Chapelle syndrome, is a DSD in which the gonadal sex (i.e.male
phenotype) does not match the chromosomal sex (i.e. 46,XX).
Literature records of the first such case return to 1964 when
Albert de la Chapelle first described it, and until now, few cases
have been reported.
1
The incidence is 1:20,000 to 25,000 male
infants and is further categorized into SRY-positive or SRY-
negative individuals, depending on the presence or absence of
the sex-determining region Y gene (SRY).
2,3
The clinical pre-
sentations of these patients are variable. Patients may present
in early life with undescended testes, micropenis, hypospadias,
and the presence of residual embryonic remnants of the
Mu
¨llerian duct structures. Later, patients may present with
failed puberty or infertility with preserved male internal
and external genitalia.
4
The diagnosis of DSD involves a
*Corresponding author.
E-mail address: bkcdc@yahoo.co.in (B.K. Chakrabarty).
Available online at www.sciencedirect.com
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medical journal armed forces india xxx (xxxx) xxx
https://doi.org/10.1016/j.mjafi.2023.08.008
0377-1237/©2023 Director General, Armed Forces Medical Services. Published by Elsevier, a division of RELX India Pvt. Ltd. All rights
reserved.
Please cite this article as: Saraswat A et al., An offbeat presentation of pri mary male infertility: de la Chapelle syndrome, Medical Journal
Armed Forces India, https://doi.org/10.1016/j.mjafi.2023.08.008

multi-disciplinary approach and the use of different upcoming
molecular techniques.
Case report
A 29-year-old healthy male patient presented to our center
with the inability to father a child after 3 years of marriage and
1 year of unprotected sexual intercourse. The patient, being
the youngest, was born into a family of six children, two
males, and four females. He had a normal childhood with no
developmental milestone delay, no history of testicular injury,
or delayed puberty. He shows a normal male phenotype with
no structural defects in the penis and testis. On anthropom-
etry, the patient's height is 169 cm and weighs 94 kg. His BMI,
as calculated, comes out as 32.9. His axillary and pubic hair
show normal development. He had no gynecomastia. Other
system examinations revealed no abnormality clinically.
His seminal fluid analysis showed azoospermia. His hor-
monal study showed:
Luteinizing hormone (LH) e13.43 mIU/ml (normal range
1.1e7 mIU/ml), follicular stimulating hormone (FSH) e11.53
mIU/ml (normal range 1.7e12 mIU/ml), prolactin 5.76 ng/ml
(3e25 ng/ml), and testosterone 3.17 ng/ml (normal range
3e16 ng/ml). The thyroid profile was within normal limits. An
ultrasound scan of the abdomen and pelvis showed no gross
abnormalities. An ultrasound scan of the testis showed the
presence of grade II varicocele on both sides with normal
testis and epididymis.
Karyotyping performed on peripheral blood mononuclear
cells showed 46,XX chromosomal complement and fluores-
cence in situ hybridization (FISH) test performed on interphase
cells with centromeric XY probe report showed two hybridi-
zation signals (SG) for the X chromosome and no signal (SO)
for the Y chromosome, consistent with karyotype analysis
(Fig. 1). Metaphase FISH performed with SRY FISH probe
showed SRY gene is positive on chromosome X and therefore
suggesting the presence of cryptic t(X; Y).
The chromosomal microarray analysis showed a loss
(896 Kb) involving chromosome X at cytoregion Xp22.33,
indicating monosomy for this region. This segment also in-
cludes the ARSL gene. There is also the presence of bands
(3.7 Mb) and (2.6 Mb), which co-localizes with cytoregion
Yp11.31p11.2 and Yp11.2, respectively. This segment also in-
cludes the SRY gene. Translocation of a segment of the Y
chromosome containing the SRY gene (480,000; Yp11.3) to the
X chromosome causes 46, XX sex reversal and 46, XX true
hermaphroditism. Homozygosity for contiguous SNP alleles
was also detected on chromosome 3. Based on the patient's
complete hormonal and cytogenomic workup, he was finally
diagnosed with a case of de la Chapelle Syndrome.
The couple was counseled adequately in explicit terms to
make them aware of the condition and the options to achieve
parenthood. After much deliberation, the couple opted for
donor sperm. The couple underwent ovulation induction and
intrauterine insemination (IUI) with donor sperms at our
center and was conceived in the first cycle. Pregnancy was
uneventful and delivered at term healthy baby.
Fig. 1 eA) Karyogram showing 46, XX chromosomal complement. (B) FISH analysis with centromeric XY probe on
interphase cells showing two hybridization signals (SG) for the X chromosome and no signal (SO) for the Y chromosome.
(C) Chromosomal microarray analysis showed a loss (896 Kb) involving chromosome X at cytoregion Xp22.33, indicating
monosomy for this region. There is also the presence of bands (3.7 Mb) and (2.6 Mb), which co-localizes with cytoregion
Yp11.31p11.2 and Yp11.2, respectively. (D) Metaphase FISH performed with SRY FISH probe showed SRY gene is positive on
chromosome X suggesting cryptic t(X; Y).
medical journal armed forces india xxx (xxxx) xxx2
Please cite this article as: Saraswat A et al., An offbeat presentation of primary male infertility: de la Chapelle syndrome, Medical Journal
Armed Forces India, https://doi.org/10.1016/j.mjafi.2023.08.008

Discussion
Disorder of sex differentiation (DSD) encompasses a compre-
hensive group of disorders presenting inborn dissonance be-
tween sex chromosomal complement and phenotypicdisplay.
5
DSDs are categorized based on the variations in the levels of
gender description by various terminologies according to ge-
netic makeup, chromosomal configuration, type of gonad pre-
sent, hormonal level, appearanceof external genitalia, and the
presence of secondary characters, as well as legal validation
and psychological characteristics. However, in the field of
clinical genetics, the management of patients is performed as
per the classification proposed by the Paediatric Endocrinology
Society Lawson Wilkins and the European Society of Paediatric
Endocrinology. Based on karyotype, the classification in-
corporates the following categories: (1) sex chromosome DSD,
(2) 46,XX DSD and (3) 46,XY DSD.
6,7
The testicular DSD or de la
Chapelle syndrome is a rare genetically heterogenous group of
gender dysplasiaunder the subgroup of 46, XX DSD. Differential
diagnosis of 46,XX testicular DSD is ovotesticular DSD.
8
Out of
four proposed mechanisms for an etiological explanation, the
translocation of Y sequences incorporating SRY gene to an X
chromosome or any autosome is demonstrated most
frequently (90%). In this case, metaphase FISH confirmed SRY
gene got translocated on the X chromosome. SRY gene is
assumed to be responsiblefor the suppression of an inhibitor of
male gonadal development. Nevertheless, on further delibera-
tion, it was found that syndromic individuals may or may not
possess an SRY gene.However, 46, XX testicularDSD is usually a
sporadic disorder, but few familial cases have also been
recognized, suggesting autosomal recessive inheritance in
those cases. Patients in the SRY-positive cases, which is the
predominant group, usually present in adolescence or early
adulthood with complaints of shorter height, gynecomastia,
small testis, and azoospermia. During the embryonal develop-
ment in most of the mammalian species, transient SRY gene
expression is postulated to trigger a downstream of cascade
leading to the generation of testisfrom the gonadal ridge. In the
present case, the patient presented with male phenotype due to
the presence of functional SRY gene. On the other hand, azoo-
spermia leading to infertility is ascribed to the absence of
azoospermia factor region (AZF), which is located on the long
arm of the Y chromosome.
9
Hormonal evaluation of the patient
showed low normal testosterone level, normal prolactin level,
and normal thyroid function test with high normal FSH and
elevated LH level suggesting features of hypergonadotropic
hypogonadism consistent with primary testicular failure. To
understand the genetic biology of the disease and for compre-
hensive management, a complete cytogenomic workup is rec-
ommended in all 46, XX testicular DSD cases. These
investigations also help to infer that phenotype heterogeneity
seen in these cases is due to the case-wise variation in the
quantity of retained Y chromosome-specific material.
In SRY-negative cases (representing around 10% of
cases), it is postulated that the male phenotypic expression
results due to either overexpression of downstream pro-
testis genes (i.e. SOX-3, SOX-9, and SOX-10) or diminished
expression of anti-testis genes, such as DAX-1, WNT4, and
RSPO1.
10
Conclusion
de la Chapelle syndrome can significantly influence in-
dividuals'personal, social, and married lives. Though early
diagnosis would still not allow the cure of this condition, the
couple can be counseled for opting for donor sperm to miti-
gate the distress. Our study emphasized the recommendation
of performing cytogenetic evaluation in all phenotypically
normal males with azoospermia so that we should not miss
out on the diagnosis of this rare but important cause of pri-
mary male infertility.
Disclosure of competing interest
The authors have none to declare.
Acknowledgement
The authors acknowledge the contribution of Aradhana Dwi-
vedi, Medical Geneticist, Army Hospital (R&R), Delhi Cantt,
India.
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medical journal armed forces india xxx (xxxx) xxx 3
Please cite this article as: Saraswat A et al., An offbeat presentation of pri mary male infertility: de la Chapelle syndrome, Medical Journal
Armed Forces India, https://doi.org/10.1016/j.mjafi.2023.08.008