46 XX karyotype during male fertility evaluation; Case series and literature review

Abstract

Forty-six XX disorder of sex development is an uncommon medical condition observed at times during the evaluation of a man's fertility. The following is a case series and literature review of phenotypically normal men diagnosed with this karyotype. Our goal is to comprehend the patients' clinical presentation as well as their laboratory results aiming to explore options available for their management. A formal literature review through PubMed and MEDLINE databases was performed using "46 XX man" as a word search. A total of 55 patients, including those conveyed in this article were diagnosed with a 46 XX karyotype during their fertility evaluation. The patients' mean age ± s.d. was 34 ± 10 years and their mean height ± s.d. was 166 ± 6.5 cm. Overall, they presented with hypergonadotropic hypogonadism. Sexual dysfunction, reduced hair distribution, and gynecomastia were reported in 20% (4/20), 25.8% (8/31), and 42% (13/31) of the patients, respectively. The SRY gene was detected in 36 (83.7%) and was absent in the remaining seven (16.3%) patients. We found that a multidisciplinary approach to management is preferred in 46 XX patients. Screening for remnants of the mullerian ducts and for malignant transformation in dysgenetic gonads is imperative. Hypogonadism should be addressed, while fertility options are in vitro fertilization with donor sperm or adoption.

Full text

Vol. 129 No. 5 March 5, 2016
Volume 127, No. 1 Pages 1-200 January 5, 2014

Asian Journal of Andrology (2016) 18, 1–5
© 2016 AJA, SIMM & SJTU. All rights reserved 1008-682X
www.asiaandro.com; www.ajandrology.com
mosaicism for the SRY gene or possible mutation of inhibitors of
the male pattern has been postulated.9
In this study, we report a series of cases of 46XX men presenting
with infertility and perform a formal literature review of similar
cases aiming to provide a comprehensive approach for managing this
relatively rare condition.
PATIENTS AND METHODS
We reviewed the records of patients presenting for initial male
fertility evaluations during the period from 2011 to 2015 at two
institutions(Cleveland Clinic and Hamad Medical Center). We
identied six patients who were found, with genetic testing, to have
46XX karyotype. e patients’ medical records were checked for
information regarding their presentation, signicant medical problems,
biologic data, physical examination, and laboratory investigations.
Semen analysis
All patients were evaluated with semen analysis and hormonal prole.
e semen analysis was performed aer 3–5days of sexual abstinence.
Collection is done through masturbation into a clean container.
Samples were incubated at 37°C and allowed to liquefy for 30min
before analysis. e analysis was performed according to the WHO
guidelines adopted in 2010.10
Hormone prole
Hormones investigated constituted of follicular stimulating hormone
(FSH) (normal level[nl]: 1–9IU l−1), luteinizing hormone(LH)
INTRODUCTION
Infertility is a common medical problem aecting roughly one out of
six couples.1 A male factor is either responsible for or contributory
to about half the cases.2 Once conception fails to occur aer at least
12months of regular unprotected intercourse, the couple’s fertility
is oen investigated. Genetic testing in men has a distinctive set of
indications that are usually picked up during the initial workup.
Marked reduction of sperm concentration, unilateral/bilateral
absence of vas deference, and suggestive family history are inuential
factors. Chromosomal abnormalities occur in<1% of the general
population,3 however their incidence rises up to 15% in men with
infertility.4
The 46XX testicular disorder of sex development(DSD),
previously known as de la Chapelle syndrome aer its rst report
in 1964,5 comprises a small share of genetic causes of male
infertility. It is a rare condition occurring in about 1:20000males6
and characterized by a variable degree of mismatch between the
phenotype and the genotype of the aected individual. Patients may
present seeking fertility with normal male internal and external
genitalia, or may present at an earlier age because of ambiguous
genitalia. Undescended testes, micropenis, and hypospadias are
commonly reported,7 as well as residual remnants of the mullerian
tract.8 What preserves a male phenotype in these individuals is
translocation of the sex‑determining region Y gene(SRY) into a sex
chromosome or an autosome, a process occurring in about 80% of
cases.9 In the remaining SRY‑negative patients, presumed hidden
ORIGINAL ARTICLE
46 XX karyotype during male fertility evaluation;
case series and literature review
Ahmad Majzoub1,2, Mohamed Arafa3, Christopher Starks4, Haitham Elbardisi2, Sami Al Said2,
Edmund Sabanegh Jr1
Forty‑six XX disorder of sex development is an uncommon medical condition observed at times during the evaluation of a man’s
fertility. The following is a case series and literature review of phenotypically normal men diagnosed with this karyotype. Our
goal is to comprehend the patients’ clinical presentation as well as their laboratory results aiming to explore options available for
their management. A formal literature review through PubMed and MEDLINE databases was performed using “46 XX man” as a
word search. A total of 55 patients, including those conveyed in this article were diagnosed with a 46 XX karyotype during their
fertility evaluation. The patients’ mean age ± s.d. was 34 ± 10 years and their mean height ± s.d. was 166 ± 6.5 cm. Overall, they
presented with hypergonadotropic hypogonadism. Sexual dysfunction, reduced hair distribution, and gynecomastia were reported
in 20% (4/20), 25.8% (8/31), and 42% (13/31) of the patients, respectively. The
SRY
gene was detected in 36 (83.7%) and
was absent in the remaining seven (16.3%) patients. We found that a multidisciplinary approach to management is preferred in
46 XX patients. Screening for remnants of the mullerian ducts and for malignant transformation in dysgenetic gonads is imperative.
Hypogonadism should be addressed, while fertility options are
in vitro
fertilization with donor sperm or adoption.
Asian Journal of Andrology (2016) 18, 1–5; doi: 10.4103/1008-682X.181224; published online: 10 June 2016
Keywords: hypogonadism; infertility; male; sex‑determining region; XX disorders of sex development
1Cleveland Clinic Foundation, Department of Urology, Cleveland, Ohio, USA; 2Hamad Medical Corporation, Department of Urology, Qatar; 3Cairo University, Department of
Andrology, Giza, Egypt; 4Reston Hospital, Department of Urology, Virginia, USA.
Correspondence: Dr. A Majzoub (dr.amajzoub@gmail.com).
Received: 16 November 2015; Revised: 21 January 2016; Accepted: 10 March 2016
Open Access
Male Fertility

Asian Journal of Andrology
46XX DSD
A Majzoub et al
2
(nl: 1–9IU l−1), prolactin (nl: 2–14 ng ml−1), total testosterone
(nl: 220–1000ng dl−1), and estradiol(nl: 10–60pg ml−1).
Cytogenetic and FISH investigations
Genetic testing in the form of karyotype and Y chromosome
micro‑deletion analysis was performed on all patients according
to practice guidelines. Aconventional chromosome analysis was
performed from patients’ peripheral blood lymphocytes, which were
cultured in RPMI 1640 medium, phytohemagglutinin, and fetal bovine
serum for 72h, followed by treatment with 50 μg ml−1 colcemid.
Metaphase chromosome spreads were studied by standard GTG and
CBG banding procedures, which included using trypsin and Giemsa for
G‑banding and barium hydroxide for C‑banding. FISH was performed
on thirty metaphase chromosome spreads using a mixture of probes
specic for DXZ1 and DYZ3, and a chromosome‑specic probe for
CBFB GLP 16 banding at 16q22. Multiplex PCR amplication of
nine sequence‑tagged site markers was used to detect AZF region
micro‑deletions on the Y chromosome.
Literature review
A formal literature review was performed using PubMed and
MEDLINE databases for the period from 1964 to 2015. e search
word “46XX man” was used. Search results were reviewed for
relevance and quality. e inclusion criteria were studies reporting
adult patients presenting with infertility and in English language. Case
reports of patients of pediatric age group as well as those investigated
for reasons other than infertility were excluded. e Institutes’ Ethics
Committee accepted the research, and a waiver of signed informed
consent was used.
RESULTS
Six patients were found to have 46XX karyotype and were included
in this study. e patients’ mean age± s.d. was 34.3± 4.5 years.
Anormal male phonotype was detected in all except one patient who
had a eunuchoid habitus characterized by increased fat distribution,
reduced virilization, and gynecomastia. e patients’ mean testicular
volume±s.d. was 5.5±1.8ml. All patients presented with primary
infertility and had normal volume azoospermia on semen analysis.
Hormone analysis revealed hypergonadotropic hypogonadism with
a mean testosterone, FSH, and LH ± s.d. of 158.8± 107 ng dl−1,
22.2±11.2IU l−1, and 14.2±5.7IU l−1, respectively. FISH conrmed
the presence of a translocated SRY region on the long arm of the X
chromosome in ve patients and its absence in the sixth patient. Other
characteristics of their presentation are shown in Table1.
e literature search resulted in 152 articles. Aer meticulous
review, 29 papers met the inclusion criteria and contained 49patients
with 46XX DSD. Tab le  1 displays all literature cases, including
those reported in this study, of 46XX men diagnosed during fertility
evaluation. e reported mean age±s.d. was 34±10years. Sexual
dysfunction, reduced hair distribution, and gynecomastia were reported
in 21%(4/19), 26.6%(8/30), and 40%(12/30) of patients, respectively.
Patients’ mean height± s.d. was 166±6.5cm. Overall, patients had
hypergonadotropic hypogonadism with a mean testosterone± s.d.
of 274.3± 135.3ng dl−1, mean FSH± s.d. of 40.4±22.2, and mean
LH±s.d. of 23.4±13.4. FISH was performed in 43patients. e SRY
gene was detected in 36 (83.7%) and was absent in the remaining
7(16.3%) patients. e translocation was to a sex chromosome in
95%(38/40) and to an autosome in 5%(2/40) of the patients. In two
out of the seven SRY‑negative patients, the authors investigated the
DAX1 and SOX9 genes and failed to detect any mutation. Testicular
atrophy was reported in all cases while testis biopsy was performed in
ten patients and showed absence of spermatogenesis with Sertoli cell
only and Leydig cell hyperplasia.
DISCUSSION
46XX DSD is a genetic abnormality infrequently encountered by
andrologists during fertility evaluation of phenotypically normal males.
Once encountered, a thorough understanding of all its implications is
mandatory for adequate management and counseling. Several etiologic
theories have been proposed to help understand this condition. In
SRY ‑positive patients, cross‑over between pseudoautosomal regions
of sex chromosomes is believed to occur during paternal meiosis.11
Whereas in SRY‑negative patients, the link remains unclear. Some
have advocated the presence of different sex determining genes
located on autosomes initiating “maleness.”12 For example, SOX9
gene, which is located on the long arm of chromosome 17, is known
to potentiate SRY gene eects and its overexpression has been linked
to 46XX SRY ‑negative males.13 Others believe that the SRY gene is in
fact inhibitory to other autosomal genes, termed “Z” genes, that are
themselves inhibitory to male sex determination.14 Furthermore, an
X‑linked dosage‑sensitive sex reversal locus has been identied and
functions as a repressor of male pathway. Meeks etal. conrmed that
mutations to the DAX1 gene would lead to 46XX female‑to‑male
sex reversal.15 Of all the cases of 46XX DSD reported in men seeking
fertility, the SRY gene was present in 83.7% and absent in 16.3%. Two
cases performed PCR amplication of the SOX9 and DAX1 regions
and failed to nd any mutation. Unfortunately, these mutations were
also not assessed in our SRY‑negative patient.
A number of characteristic features are picked up during physical
examination but are not sufficient to make a diagnosis. Unlike
Klinefelter patients(47XXY) who can present with similar complaints,
patients with 46XX DSD generally have a short stature which is
mainly due to lack of testosterone‑driven pubertal growth spurt or
due to absence of other Y‑chromosome specic growth factors.16 e
mean height±s.d. of reported cases in this review was 166±6.5cm.
e degree of virilization is variable. While it is complete in some
patients, others may have poor hair growth, female fat distribution,
and gynecomastia secondary to an altered testosterone/estradiol ratio.
is imbalance is thought to result from an increase in peripheral
aromatization of testosterone. Anding that is inuenced by the
increase in fat mass and the decrease in lean muscle mass, which
is oen seen in many chromosomal disturbances with subsequent
hypogonadism.17 is variability can be explained by the hypogonadism
oen in existent or may be secondary to a dose‑dependent genetic
aberration, as has been postulated by some researchers.18 Up to 40%
of cases had some form of reduced virilization.
Testicular atrophy is always detected on genital examination, in
addition to other less frequent abnormalities such as undescended
testis and hypospadias,19 which have been reported in 5.5% and 7.4%
of cases in this review.
Azoospermia is present on semen analysis as would be expected
since all Y chromosome azoospermia factors(AZF) are lacking.20
Serum hormone testing reveals hypergonadotropic hypogonadism
consistent with primary testicular failure. The mean ± s.d. of
serum testosterone, FSH, and LH reported in all cases were
274.3± 135.3 ng dl−1, 40.4±22.2IU ml−1, and 23.4± 13.4 IU ml−1,
respectively. Once karyotype analysis fails to detect a Y chromosome
in a phenotypic male, FISH or molecular amplication by polymerase
chain reaction(PCR) is performed to look for the presence or absence
of SRY gene. Although this workup does not have a prognostic value,
it documents the various genetic rearrangements of the syndrome.

Asian Journal of Andrology
46XX DSD
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Table 1: 46 XX DSD men presenting with infertility
References Case Clinical data Hormones Genetics Pathology
histology
Age
(years)
ED Reduced
HD
GM Penis
size
(cm)
Other Weight
(kg)
Height
(cm)
T
(ng dl−1)
FSH
(IU l−1)
LH
(IU l−1)
E
(pg ml−1)
PRL
(ng ml−1)
SRY Location*
Rigola et al. 200234 1 33 No No NL + Xp
Valetto et al. 200535 2 35 No No NL 48 152 306 23.9 17.7 7.13 −
Dauwerse, et al.
200611
3 61 No NL SS 171 325.4 13 10 31.3 + 16q
Kim, et al. 201533 4 29 Yes No No 10.7^ 62 165 179 76 41 − Hyalinization, LCH
Ryan et al. 201318 5 40 No Yes No 3.6φ1 10 −
Gao et al. 201336 6 163 308.7 93.6 19.4 33 17.9 + Xp
7 163 277.6 24.7 14.4 43 18.5 + Xp
8 162 129.6 + Xp
9 161 137.6 81.6 27.7 19.8 22.9 + Xp
10 158 244.5 13.1 3.61 34 9.67 + Xp
11 162 172.8 54.7 19.4 27 10.08 + Xp
12 162 319.6 37.1 16.5 28 9.88 + Xp
13 161 216 43 33.9 22 7.28 + Xp
14 160 336.9 72 34.6 19.8 10 + Xp
15 160 180.8 49 26.8 19.8 15.8 + Xp
16 161 521.2 87.7 31.4 30.5 49.6 + Xp
Xiao et al. 201337 17 27 No No NL HS 170 180 47 18.7 12 14.6 − **
Rizvi 200821 18 33 No 8.6φ85.8 177 207 46 23 + Xp
Minor et al. 200838 19 24 Yes 11.9♯55.4 28.4 + Xp
Rajender Thangaraj,
et al. 20069
20 34 No No NL 64 156 580 25.8 15.8 − **
Queralt et al. 200839 21 31 No No 58 170 323 62.2 25.8 17 + 1q
Tan et al. 1993822 32 No No Yes Small HS 176 263.2 21 34 25
Zakharia
et al. 199012
23 28 No Yes NL 65 165 240 72 61 16.3 Leydig and Sertoli
cell hyperplasia
Chiang et al. 201340 24 33 No 203 46.5 17.6 27.05 + Xp
25 34 UT 217 54.3 19.6 8.15 + Xp
26 52 HS 144 64.3 20.2 16.08 −
Wu et al. 201441 27 165 195.8 35.5 13.8 30.5 4.6 + Xp
28 162 155.5 29.2 12.9 19.1 3.6 + Xp
29 164 256.3 45.9 25.1 26.7 7.8 + Xp
30 167 241.9 33.7 22.3 29.1 10.9 + Xp
31 165 201.6 31.4 19.6 22.1 7.8 + Xp
Tomomasa, et al.
199925
32 25 No No 55 177 428.6 19.7 10.3 + Xp Hyalinization, SCO
Jain, et al. 201326 33 38 Ye s No Yes NL 63 162 120 76.6 36.3 + Xp FNA: SCO
Chernykh et al.
200942
34 37 Yes Yes 74 160 290.8 26.9 13.5 + Xp
Yencilek et al. 200527 35 26 No No No 8φ72 165 270 45.6 48.9 9.4 LCH and tubule
sclerosis
Butler, et al.198328 36 31 No No Yes 7φ72 169 477 51 + Tubular atrophy,
absent
spermatogenesis,
LCH
Castineyra et al.
200243
37 28 No Yes 180 300 50 16 28 14 + Xp
38 35 No SS,
UT
170 700 3.5 6.2 38 3.4 + Xp
39 28 Yes HS 160 140 21 5.2 19 8.1 + Xp
40 39 Yes 174 560 6.7 4.2 30 6.2 + Xp
41 24 No 172 300 45 40 20 5.4 + Xp
Fuse, et al. 199129 42 30 No No 90 172 160 47 60 + Xp Germinal aplasia,
LCH
Pais et al. 197730 43 29 No No Yes Small 82 170 267 53 45 Hyalinization,
SCO, LCH
Wegner et al. 198331 44 35 No No NL 81 167 630 23.7 37.1 3.8 + Xp SCO, LCH
Micic et al. 198332 45 25 No Yes No 63 171 319.6 31 18 47 6.8 SCO, LCH
Contd...

Asian Journal of Andrology
46XX DSD
A Majzoub et al
4
SRY ‑negative patients are believed to have a higher frequency of genital
ambiguities,21 this particular association was not found in this subset
of 46XX DSD patients.
A multidisciplinary approach to management is favored aer
reaching the diagnosis. Genetic counseling is required to help the
patient and his partner understand various aspects of his condition, in
addition to psychological support, which would ease his comprehension
of dicult information. Imaging of the pelvis is required to look for
remnants of mullerian ducts that may cause morbidity in the form
of repeated infections or urinary incontinence22 and require surgical
removal. Neoplastic transformation(gonadoblastoma) of dysgenetic
gonads has been described in up to 30% of cases specically when Y
chromosome material is detected.23 As such, serial self‑examinations
should be encouraged together with regular gonadal ultrasound
imaging. Repeated gonadal biopsy and even gonadectomy in
nonfunctioning gonads have also been proposed to overcome the
risk of malignancy.24 Testicular biopsy has been reported in ten
cases displaying unied absence of germinal cells and Leydig cell
hyperplasia.12,25–33 Surgical correction of genital ambiguities such as
hypospadias and undescended testis is required. Cosmetic surgery for
gynecomastia should also be considered if the patient desires.
e patient’s hypogonadism should be managed with testosterone
replacement. erefore, discussion about dierent forms of testosterone
therapy and their possible side eects should be considered early
aer diagnosis. Prior to initiating therapy, a baseline bone density
scan(DEXA) should be performed to look for osteopenia or
frank osteoporosis. Patients with a T score of <−1.0 would benet
from treatment with Vitamin D and calcium, bisphosphonates, or
calcitonin, and require annual repeats of DEXA scan until results
are normal.19 As regards to fertility, options are limited to articial
insemination or invitro fertilization using donor sperm or resolving
to adoption.
CONCLUSION
46XX DSD is a rare genetic disorder that is seldom picked up during
evaluation of patients with infertility. An understanding of all aspects
of this condition is certainly required for oering the most suitable
treatment. Herein, we report the largest single report case experience
as well as the largest review of worldwide experience with 46XX DSD
detected during fertility evaluation.
AUTHOR CONTRIBUTIONS
AM participated in the acquisition of data, summarized the collected
evidence, and draed the manuscript. MA designed the study and
participated in the acquisition of data. SC participated in the acquisition
of data. HA revised the manuscript and helped in coordination. SA
revised the manuscript and helped in co‑ordination. ES helped to
dra the manuscript and provided supervision. All authors read and
approved the nal manuscript.
COMPETING INTERESTS
e authors declare no competing interests.
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Table 1: Contd...
References Case Clinical data Hormones Genetics Pathology
histology
Age
(years)
ED Reduced
HD
GM Penis
size
(cm)
Other Weight
(kg)
Height
(cm)
T
(ng dl−1)
FSH
(IU l−1)
LH
(IU l−1)
E
(pg ml−1)
PRL
(ng ml−1)
SRY Location*
Matthews et al.
198344
46 27 Yes No UT,
FFD
68 166 282.2 46 19 33 9.87
Pepene et al. 200845 47 28 No No Yes FFD 65 167 333.2 43.9 25.3 + Xp
Hado et al. 200346 48 76 No No Yes 157 259 27.8 21 + Xp
Mustafa et al. 201047 49 30 No Ye s NL 75 170 211 40.7 16.6 8.5 −
Current study 50 40 No No No NL 84 175 335 38 12 29 13.6 + Xp
51 31 No No No NL 129 14 6 25 3.2 + Xp
52 35 Ye s Yes Ye s NL 74 10 23 5.7 + Xp
53 29 No No No NL 77 181 246 13.4 12 19 + Xp
54 39 No No No NL SS 74 160 74 28 15 −
55 32 No No Yes NL 86 170 95 29.7 16.9 12 + Xp
*Methods used for detection of SRY were fluorescence in situ hybridization, polymerase chain reaction, DNA hybridization, and high resolution banding; ^Erect length; φFlaccid length; ♯Free
testosterone (pg ml−1); **DAX1 and SOX9 genes amplified and reported as normal. ED: erectile dysfunction; HD: hair distribution; T: testosterone; LH: luteinizing hormone; FSH: follicular
stimulating hormone; E: estradiol; PRL: prolactin; SRY: sex determining region Y gene; SS: hypoplastic scrotum; HS: hypospadias; UT: undescended testis; FFD: female fat distribution;
LCH: leydig cell hyperplasia; GM: gynecomastia; DSD: disorder of sex development; NL: normal level

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22 Morgan RJ, Williams DI, Pryor JP. Mullerian duct remnants in the male. Br J Urol
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