Annales d’Endocrinologie 72 (2011) 239–243

Original article

45,X/46,XY mosaicisme: Report of five cases and clinical review

Mosaïcisme 45,X/46,XY : à propos de cinq cas et revue de littérature
N. El Moussaif a,∗ , N. El Haddad a , N. Iraqi a , A. Gaouzi b
a
Service d’endocrinologie diabétologie, CHU d’Avicenne, Souissi, Rabat, 10000 Maroc
b Unité d’endocrinologie pédiatrique, service de pédiatrie IIA, hôpital d’enfants, CHU d’Avicenne, Souissi, Rabat, 10000 Maroc

Résumé
Introduction. – Le mosaïcisme 45,X/46,XY est une anomalie gonosomique du déterminisme sexuel caractérisé par un très large spectre phénotypique
allant de femmes avec ou sans stigmates turnériens, aux hommes d’apparence normale en passant par les phénotypes ambigus avec un degré variable
de masculinisation des organes génitaux externes. Du point de vue histologique, plusieurs situations peuvent se présenter. Patients et méthodes. –
Nous rapportons cinq observations de patients ayant un mosaïcisme à caryotype 45,X/46,XY. Nous avons analysé les données cliniques, biologiques,
échographiques et génitographiques ainsi que les constatations peropératoires et le traitement effectué chez ces patients. Résultats. – L’âge moyen
de nos patients était de 6,6 ans, deux avaient un phénotype féminin avec hypertrophie clitoridienne (dont l’une d’elles avec stigmates turnériens),
un avait un phénotype masculin normal avec cryptorchidie bilatérale et deux une ambigüité des organes génitaux externes, ces deux derniers ont
été assignés au sexe masculin. Un retard statural était noté chez quatre patients. L’exploration chirurgicale a permis de retenir le diagnostic de
dysgénésie gonadique mixte chez quatre de nos patients. Aucun cas de gonadoblastome n’a été rapporté, chez les deux filles une gonadectomie
prophylactique a été réalisée, chez les garçons la streak gonade a été réséquée et le testicule dysgénétique biopsié et préservé sous réserve d’une
surveillance assidue. Conclusion. – Cette hétérogénéité souligne l’importance d’une évaluation clinico-histologique précise chez tout patient
présentant un caryotype 45,X/46,XY.
© 2011 Elsevier Masson SAS. Tous droits réservés.

Mots clés : Dysgénésie gonadique mixte ; Mosaïcisme 45, X/46, XY ; Phénotype ; Syndrome de Turner ; Anomalies du chromosome Y

Abstract
Introduction. – The mosaicism 45, X/46, XY is a gonosomal abnormality characterized by a broad phenotypic spectrum, ranging from women
with or without Turner syndrome stigmata, to men apparently normal, passing by the ambiguous phenotypes with variable virilisation of external
genitalia. From the histological point of view, several situations may arise. Patients and methods. – We analyzed the clinical, hormonal, sonographic,
and genitographics data, as well as peroperative and histological findings for five cases of mosaicism 45, X/46, XY, and we discussed treatment
performed. Results. – The mean age of patients was 6.6 years, two had a female phenotype with clitoral hypertrophy (one of them had Turner
syndrome stigmata), one had a normal male phenotype with bilateral cryptorchidism and two had an ambiguity of external genitalia assigned to
male. Short stature was noted for four patients. Surgical exploration concluded to the diagnosis of mixed gonadal dysgenesis for four of our patients.
No cases of gonadoblastoma have been reported, for girls a prophylactic gonadectomy was performed, for boys the streak gonad was resected
and the dysgenetic testis biopsied and preserved, subject for constant monitoring. Conclusion. – This heterogeneity indicate the importance of an
accurate clinical and histological evaluation of any patient presenting with 45, X/46,XY mosaicism.
© 2011 Elsevier Masson SAS. All rights reserved.

Keywords: Mixed gonadal dysgenesis; 45, X/46, XY; Phenotype; Turner’s syndrome; Y chromosome abnormalities

1. Introduction

Mosaicism is defined by the presence in the same individ-

∗ Corresponding author.
ual, of two or more cell populations derived from a single stem
E-mail address: angelinaa74@hotmail.com (N. El Moussaif). cell line, but with a different composition of chromosomes.

0003-4266/$ – see front matter © 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ando.2011.04.009

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 240 N. El Moussaif et al. / Annales d’Endocrinologie 72 (2011) 239–243
45,X/46,XY mosaicism is an extremely rare disorder, its inci-
dence for the general population varies between 1.5/10,000
and 1.7/10,000 depending on the series [1,2]. It combines a
very wide range from phenotypic women with and without
Turner syndrome stigmata, to men apparently normal through
the ambiguous phenotypes with varying degrees of masculin-
isation of external genitalia. With this karyotype, histological
abnormalities are present in 27% of men with normal masculin-
ization of external genitalia [2]. In addition to the almost constant
persistence of Mullerian ducts, several situations may arise: nor-
mal testis [3], simply reducing the size of seminiferous tubules
or the number of germ cells [4], streaks gonads [5], a dysge-
netic testis and the other streak gonad defining mixed gonadal
dysgenesis (as originally proposed by Sohval in 1963 [6]), two
dysgenetic testis defining partial gonadal dysgenesis [7], or
more rarely coexistence of testicular tissue (seminiferous) and
ovarian tissue (stroma with follicles) leading to ovotestis diag-
nosis [5]. For patients with 45,X/46,XY karyotype, medical care
includes not only problems of ambiguous phenotypes caused by
the choice of gender, prophylactic gonadectomy or genitoplasty,
but also problems related to Turner syndrome resulting from the
presence of 45X cell population.
2. Patients and methods
We report five cases of patients with mosaic 45, X/46, XY
collected at the Pediatric Endocrinology unit of the Avicenne
hospital in Rabat on a period from 2000 to 2010. We analyzed
the clinical, hormonal, sonographic, and genitographics data, as
well as peroperative and histological findings of these patients.
3. Results
The results of the observations are shown in Table 1.
4. Discussion
The mosaic 45,X/46,XY may be due to a structural abnor-
mality of the Y chromosome, that is predisposing either to late
anaphase migration during the first mitotic division resulting
directly in a mosaic 45,X/46,XY or to the mitotic no disjunction
with formation of three cell lines XO, XY, XYY and subsequent
loss of the XYY line [8,9]. The phenotypic consequences of
mosaicism 45X/46XY does not seem to be related to the pro-
portion of two cell populations as it was originally proposed [10].
Mosaicism found in lymphocytes (karyotype of the patient), or
the amniotic cells (amniocentesis) does not reflect the proportion
of gonadal mosaicism and is not correlated to clinical pheno-
type [1]. It does not seem also that there is a match between
gonadal karyotype and the gonad differentiation degree, the the-
ory suggesting that gonadal sex determination in the mosaics is
consistent with the predominance of cell population contained
in a given gonad has not been confirmed [10]. Pierre et al. [11]
proposed another theory, which suggests that the distribution
of the X0 and XY cell populations that existed at the criti-
cal testicular differentiation has disappeared thereafter, or that
the level of mosaicism may be still present in the body, but is
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difficult to detect. The mosaic 45X/46XY most often leads to a
mixed gonadal dysgenesis (MGD) [9,11], this was the case for
four of our patients, no similar case in their family was noted.
However, as previously stated, other histological situations are
possible [5,7], so the mosaic karyotype is not a necessary condi-
tion for the occurrence of MGD. The description of familial
cases [12], and the presence of patients with XY karyotype
without MGD Mosaic [5,7] suggests that it is an entity of het-
erogeneous etiology, failure of testicular development could be
underpinned by determination errors or postzygotic testicular
differentiation, but studies in this direction have not been able to
determine the existence of mutations in the SRY gene that may
explain this heterogeneity [7,10]. Mizuno et al. [13] analyzed
the SRY sequence in gonadal for five patients with MGD and
noted its absence at the streak gonad of two patients, although
it was positive both in the karyotyping blood and in testicu-
lar skin cells. Thus, the SRY gene is the point of initiating a
complex cascade of molecular events involving opposing forces
and crucial alliances before reaching the gonadal sex determi-
nation. Several mutations in other genes (PAX2, EMX2, Lhx9,
WT1, GATA4, SOX9, SF1, DAX1, etc.) as well as duplication of
the dosage sensitive sex (DSS) have been described in cases of
gonadal dysgenesis, but the testicular dysfunction was always
accompanied by other abnormalities [5]. If the molecular mech-
anisms are still unclear, one thing is certain, the phenotype
is the result of the degree of testicular function, its ability to
masculinizing the external genitalia and to regress Mullerian
ducts. The discovery of SRY was promising. Since then, and
despite more than 20 years of work, few data about this gene
are known. The fact that SRY is on the Y chromosome makes
it vulnerable to degradation, therefore it is not very well con-
served and shows some functional gaps. This is surprising for
a gene from which the specie continuity is so dependent [5].
Indeed, some microdeletions of the Y may be accompanied by
a high mitotic instability, promote its loss before the period of
embryonic gonad differentiation and lead to the formation of
mosaic [14,15]. It is therefore necessary before proposing med-
ically assisted reproduction to infertile men to identify these
anomalies and to measure the risk [16]. It is well known that
the MGD can put them at risk of developing gonadoblastoma,
seminoma and of dysgerminoma [3]. This risk is estimated at
one third of cases [10], it is maximum around puberty [2]. But
the choice of ablation of the gonads is not always easy, if the
female is better suited to this state of castration, in males, the
risk of degeneration must be balanced against the functional
capacity of the gonad, and the psychological impact of gonadec-
tomy. In our two patients assigned to the female (no 4 and no 5),
gonadectomy was immediately performed by laparoscopy. In
patient no 1 Fig. 1 and 2.the right gonad is normally in place, we
kept it based on the data suggesting that no cases of tumor have
been reported in normally descended testes [17]. In patient no 2,
the streak gonad was resected, the contralateral gonad preserved
and lowered, subject to constant monitoring. Its biopsy didn’t
reveal any signs of malignancy. Few studies have examined the
long-term intra-abdominal gonads lowered [18]. There is no
consensus dictating the best attitude to take. Some authors pre-
fer gonadal biopsy, others argue for prophylactic gonadectomy
 N. El Moussaif et al. / Annales d’Endocrinologie 72 (2011) 239–243 241

Table 1
Summary of the five observations.
Résumé des cinq cas.
Observation no 1 no 2 no 3 no 4 no 5

Age 14 months 10 years 7 years 3 years 12 years

Sex assignment Male Male Male female Female
Size −2DS −2DS Normal −4DS > −4DS
external genitalia:
Glans(cm) 2/1 4/2 2/1,5 2.5/1 1.5/1
Labio-scrotal swelling Asymmetric Scrotal Intermediate Female Female
Orifices Vulvar Hypospadias meatus Posterior Vulviforme Vaginal and
hypospadias hypospadias urethral
Gonads Right palpated Cryptorchid Cryptorchid Not palpated Not palpated
Karyotype 45X/46XY 45X/46XY(ring Y) 45X/46XY 45X/46XY 45X/46XY
Testosterone after HCG < 0,1 ng/mL 2,8 ng/mL 0,14 ng/mL 0,36 ng/mL < 0,1 ng/mL – Normal for sex
0,56 ng/mL – –
Ultrasound Contralateral gonad and Gonads and Mullerian Uterus + vagina Ovaries not Prepubertal uterus
Mullerian ducts not ducts not visualized Gonads not visualized ovaries and
visualized visualized fallopian not
visualized
Génitography Male urethra + picture Vaginal cavity + uterine Vaginal cavity Vaginal cavity –
addition to suspect cavity + fallopian tubes uterine cavity uterine cavity
mullerian ducts
Laparoscopy Hemiutérus + gonad Rudimentary uterus 2 – Rudimentary Reduced uterus
hypoplastic left fallopian Right gonad Uterus reduced reduced Gonads
Vaginal canal Gonads
Treatment Hypospadias surgery Hypospadias surgery – Bilateral Bilateral
attaching the right gonad removal of Mullerian gonadectomy gonadectomy
ablation of hemiutérus ducts Gonads placed Vaginoplasty
and left gonad above the inguinal Clitoridoplasty
(pedicle short)
Histology Streak Streak – Streak Streak
gonad + Dysgenetic testis gonad + Dysgenetic testis gonad + Dysgenetic gonad + Dysgenetic
testis testis
Diagnosis retained MGD MGD – MGD MGD

MGD: Mixed gonadal dysgenesis.

at puberty [2]. Risk assessment of degeneration could be done

through PCR research of the gene TSPY (Testis Specific Pro-
tein Y-encoded). This gene is linked to the development of
gonadoblastoma, seminoma and the other tumors [15]. Recently,
another gene involved in the genesis of gonadoblastoma has been

Fig. 2. Case no 1. Genitography: male urethra and picture addition to suspect

Fig. 1. Case no 1. Asymmetrical appearance of the external genitalia at exami- Mullerian duct.
nation. Aspect à la génitographie: urètre de type masculin et image d’addition faisant
Aspect asymétrique des organes génitaux externes à l’examen. suspecter des dérivés mulleriens.

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 242 N. El Moussaif et al. / Annales d’Endocrinologie 72 (2011) 239–243
Fig. 3. Case no 5. Clitoral hypertrophy measuring 1.5 cm with urethral and
vaginal orifices.
Hypertrophie clitoridienne de 1,5 cm avec deux orifices urétral et vaginal.
described OCT 3/4 [18]. Explorations such as non-invasive ultra-
sound and testicular tumor markers are always recommended.
Given the key role of sex steroids in the acquisition and mainte-
nance of bone mass, the potential impact on bone metabolism of
congenital hypogonadotropic leaded to different studies. These
diseases are rare; the consequences of bone gonadal dysgenesis
were studied mainly in the two most common types, including
Turner syndrome and Klinefelter syndrome. Regarding other
etiologies, in this case the MGD, we know no studies that have
been published on this subject. If we know that in Turner, there
is bone loss associated with a hyper remodelling, that seems to
be correlated with hormonal status, what about the other pheno-
types karyotype 45X/46XY? Any ways, the predominant factor
in the genesis of bone loss is the lack of sex steroids and not
the chromosomal abnormality [19], thus an assessment of bone
mineral density seems to be needed for patients 45, X/46, XY,
all phenotypes combined. On the pubertal, no cases of spon-
taneous puberty or pregnancy have been reported in women
with MGD 45, X/46, XY [5], moreover, because of the pres-
ence of Y material, gonadectomy is most frequently performed
at a very young age. For men, if spontaneous puberty is possi-
ble sometimes, infertility appears in most of the cases however
later. [16]. In our series, puberty will artificially be induced in
both females (no 4, no 5) Fig. 3 from a bone age of 12, by a
natural estrogen dose-escalation, and in combination with pro-
gestin two years after. In patients without uterus the addition
of progestin is unnecessary [18]. Sex assignment in the MGD
is still debatable. For patients 1, 2, and 3 assigned to the male,
we have no long-term monitoring to judge their future puberty.
Patient no 2 has satisfactory degree of masculinization of exter-
nal genitalia that may be consistent with the choice of males.
But in case 3, the low degree of masculinisation, and the lack of
response from the glans at HCG test, may challenge the award
of the male in his case. In the David et al. serie [20], which
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had included 15 patients with MGD, the sex male choice was
done for six patients. This approach has been regretted in most
of them due to the small size, the iterative genitoplasty and the
poor performance of pubertal testicular function. This brings us
back to the difficulties observed with the ambiguous phenotypes
related to delayed diagnosis in our context. The average age of
diagnosis in our series is 6.6 years and the sex of assignment
is usually assigned by parents and not by the medical profes-
sion, thus our attitude is limited to genitoplasty consistent with
the original sex assigned, because it would be fastidious to go
back on sex selection, knowing the psychological impact that
might have this kind of decision, both on parents and the child
who was already building a sexual identity. Concerning growth,
four of our patients had a deficit stature; in girls (case no 4 and
no 5) the delay was estimated at less than or equal to 4DS, less
severe in boys − 2DS (case no 1 and no 2), case no 3 had a nor-
mal size for her age and gender. We have treated with growth
hormone cases no 4 and no 5. The small size is generally better
tolerated in girls, with unquestionable benefit of treatment with
growth hormone [20]. If the karyotype is systematically applied
to small girls, it’s not the same for boys. According to the review
of amniocentesis, the percentage of male phenotype with appar-
ently normal karyotypes 45, X/46, XY is estimated at 90% [1],
the small size, however, is common for these patients. This leads
some authors to include it among the exams exploration of short
stature for boys, the goal is to enable an early diagnosis for
better prognosis for final height after treatment [21]. However,
we think it would be more logical to apply it only to cryp-
torchidism, hypospadias, micropenis, and obviously to cases of
Turner syndrome stigmata. Finally, we must emphasize that the
management of patients with mosaicism 45, X/46, XY, should
also include diagnosis and monitoring of the manifestations
of Turner syndrome, especially cardiac anomalies that can be
life-threatening.
5. Conclusion
There are rare forms of gonosomal abnormalities whose
management requires a multidisciplinary team involving pedi-
atric, endocrinologist, surgeon and psychologist. Indeed, in the
ambiguous phenotypes, the decision regarding the assignment
of sex must be taken as soon as possible. The occurrence of
such a situation is difficult for parents, how it is experienced
depends on personal and cultural factors, it can affect how the
child is invested by his parents and therefore affect his psycho-
logical development. Only an extended follow-up of cases of
mosaicism 45, X/46, XY diagnosed prenatally, can help to bet-
ter assess their long-term outcome on the quality of life, the
risk of degeneration, the bone capital, growth, pubertal devel-
opment, sexual dysfunction, fertility, mental health, self-esteem
and relationship skills.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
 N. El Moussaif et al. / Annales d’Endocrinologie 72 (2011) 239–243
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