J C E M
O N L I N E
A d v a n c e s
i n
G e n e t i c s — E n d o c r i n e
R e s e a r c h
45,X/46,XY Mosaicism: Phenotypic Characteristics,
Growth, and Reproductive Function—A Retrospective
Longitudinal Study
Marie Lindhardt Johansen, Casper P. Hagen, Ewa Rajpert-De Meyts,
Susanne Kjærgaard, Bodil L. Petersen, Niels E. Skakkebæk, Katharina M. Main,
and Anders Juul
Department of Growth and Reproduction (M.L.J., C.P.H., E.R.-D.M., N.E.S., K.M.M., A.J.), Department
of Clinical Genetics (S.K.), and Department of Pathology (B.L.P.), Rigshospitalet and Copenhagen
University, DK-2100 Copenhagen, Denmark
Context: Most previous studies of 45,X/46,XY mosaicism are case reports or have described single
aspects of the disease.
Objective: The objective was to provide longitudinal data of patients with 45,X/46,XY mosaicism.
Design: This was a retrospective, longitudinal study conducted from June 1990 to January 2012.
Setting: The study took place at a tertiary pediatric and andrological referral center.
Patients or Other Participants: Twenty-five patients (18 boys, seven girls) with 45,X/46,XY mosaicism and its variants were included and were compared to healthy controls.
Intervention(s): No interventions were included in the study.
Main Outcome Measure(s): Phenotypes were scored using external masculinization scores. Serum LH,
FSH,testosterone,estradiol,andinhibinBlevelswerereportedinmalepatients.IGF-Ilevelsandheightwere
reported in all patients. Available biopsies/gonadectomies were histologically examined.
Results: Fourteen of 18 males had external masculinization scores consistent with normal virilization. Ten of 11 male patients experienced spontaneous puberty. Median height SD score was ⫺2.0
(range, ⫺3 to 0.3) for males and ⫺2.2 (range, ⫺2.5 to ⫺1.4) for females, both considerably below
genetic potential. Median 1-yr height gain after GH treatment in seven patients was 0.5 SD (0.1 to
1.2). All tissue samples from 15 patients (eight males, seven females) revealed abnormal gonadal
histology. Four patients had carcinoma in situ (CIS); two had tissue samples available from early
childhood, one showing CIS.
Conclusions: Gonadal function in most 45,X/46,XY males, even those with genital ambiguity, seems
sufficient for spontaneous puberty. Short stature and 45,X/46,XY mosaicism seem associated, but
patients appear to benefit from GH treatment. Histology from two patients with biopsies from
early childhood indicates that CIS originates before puberty. (J Clin Endocrinol Metab 97:
E1540 –E1549, 2012)
T
he 45,X/46,XY karyotype is rare with an estimated
incidence rate of less than 1/15,000 live births in Denmark (1). It poses a great clinical challenge because it may
affect growth, hormonal balance, gonadal development,
and histology. The presence of the Y chromosome material in
the cell line colonizing the primitive gonadal ridge has been suggested as the determining factor for the early gonadal sex differentiation and phenotype (2–4).
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2012-1388 Received February 12, 2012. Accepted April 23, 2012.
First Published Online May 17, 2012
Abbreviations: AZF, Azoospermia factor; CIS, carcinoma in situ; CV, coefficient of variation;
EMS, external masculinization score; HRT, hormone replacement therapy; IMS, internal
masculinization score; PLAP, placental-like alkaline phosphatase; SCO, Sertoli cell-only;
SDS, SD score.
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J Clin Endocrinol Metab, August 2012, 97(8):E1540 –E1549
J Clin Endocrinol Metab, August 2012, 97(8):E1540 –E1549
jcem.endojournals.org
E1541
TABLE 1. EMS and IMS of phenotypically predominantly male patients
EMS
Patient no.
Sex
Karyotype
Scrotal
fusion
Micropenis
Urethral
meatus
Right
gonad
Left
gonad
Total
EMS
1
2
3
4
5
6
7
8
9
10
11
12
M
M
M
M
M
M
M
M
M
M
M
M
45,X关3兴/46,XY关27兴
45,X关3兴/46,XY关97兴
45,X关3兴/46,XY关13兴
45,X关4兴/46,XY关126兴
45,X关6兴/46,XY关24兴
45,X关16兴/46,XY关14兴
45,X关2兴/46,XY关29兴
45,X关182兴/46,XY关34兴
45,X关80兴/46,XY关20兴
45,X/46,X,idic(Y)(q11.23)
45,X关17兴/46,XY关30兴
45,X关22兴/46,Xdel(Y)(q12)关13兴
3
3
3
3
3
3
3
3
0
3
3
3
3
3
3
3
3
0
3
0
0
3
3
3
3
3
3
3
3
0
3
0
0
1
3
3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0
1
1
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
0
1
1.5
1.5
12
12
12
12
12
6
12
4
1
9
11.5
12
13
14
15
16
17
18
M
M
M
M
M
M
45,X关7兴/46,Xidic(Y)(p11.3)关38兴
45,X关6兴/46,XY关44兴
45,X关20兴/46,XY关80兴
45,X关30兴/46,XY关24兴
45,X关4兴/46,Xdel(Y)(q?)关26兴
45,X关10兴/46,Xidic(Y)(p)关20兴
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1.5
1.5
1
1.5
1.5
1.5
1.5
1
1.5
1.5
1.5
1.5
12
11.5
11.5
12
12
12
EMS and IMS data are as described by Ahmed et al. (13). Scores (yes/no or gradient): scrotal fusion (3/0); micropenis (0/3); urethral meatus
(normal, 3; glandular, 2; penile, 1; perineal, 0); right and left gonad (scrotal, 1.5; inguinal, 1; abdominal, 0.5; absent, 0); uterus (0/3); right and left
fallopian tube (0/2); right and left epididymis (2/0); right and left vas deferens (2/0). M, Male; R/L, right/left; Tvol, testicular volume; NA, not
applicable due to gonadectomy; pp, labeled as a prepubertal testicle in patient file; ⫺, information not available in patient file.
a
Increased nuchal fold.
b
Positive triple diagnostics (abnormal levels of serum ␣-fetoprotein, human chorionic gonadotropin and/or unconjugated estradiol).
The 45,X/46,XY karyotype represents a wide spectrum
of phenotypes, from Turner females to phenotypically
normal males with varying degrees of genital ambiguity
(5). The appearance of streak gonads, ovotestes, and other
histological abnormalities has been investigated in several
case reports, smaller studies, and in a large multicenter
histological survey (2, 4, 6).
Limited reports exist on the levels of reproductive hormones in these patients. High gonadotropin levels have,
nonetheless, been described in male and female patients, as
well as low levels of testosterone in male patients, both
regardless of genital ambiguity (2, 5, 6).
Furthermore, 45,X/46,XY patients often present with
short stature (2, 5, 7, 8).
Clinical knowledge about patients with 45,X/46,XY
mosaicism is limited. We therefore evaluated phenotypes,
reproductive hormones, puberty, gonadal histology, and
height in 25 consecutive patients with 45,X/46,XY mosaicism and its variants in a single tertiary center.
Patients and Methods
Patients
We identified all patients followed in our clinic from June
1990 to January 2012 with ICD10 codes Q96.3 (mosaicism,
45,X/46,XY), Q96.8 (other variants of Turner’s syndrome),
Q97.8 (other specified sex chromosome abnormalities, female
phenotype), Q98.7 (male with sex chromosome mosaicism),
Q98.8 (other specified sex chromosome abnormalities, male
phenotype), and Q99.8 (other specified chromosome abnormalities) in our patient registry, and evaluated 63 patient record files.
Thirty-six of these patients were excluded due to other karyotypes and two due to lack of follow-up information (missing
files). A final group of 25 consecutive patients with a confirmed
karyotype of 45,X/46,XY mosaicism were included in this study.
Patients with aberrations of their Y chromosome were also included. We divided the patients into two groups according to the
gender of rearing: 18 males and seven females.
In the patient records, we identified phenotypic characteristics at birth and during follow-up. Data on weight, length, and
gestational age at birth were available in 12 patients (eight boys).
All hormone values from the included patients (0 –20 yr) were
available from routine visits to the outpatient clinic. Only reproductive hormone serum values of the male patients were included because the data on the female patients before gonadectomy were sparse. We only included levels of reproductive
hormones in boys before sex hormone replacement therapy
(HRT). Three male patients received testosterone treatment for
puberty induction and completion, height optimization, and after gonadectomy of a remaining testicle, respectively. Height
data were not censored for puberty induction. Histological descriptions of gonadal tissues (biopsies and/or gonadectomies)
were available from 15 patients (eight males, seven females).
Karyotyping
Karyotyping was done in lymphocytes isolated from peripheral blood, and in one case in a skin biopsy, using routine Gbanding and counting of metaphases. All karyotypes were reevaluated by an experienced clinical geneticist (S.K.) and
confirmed through the Danish Cytogenetic Registry. The original metaphase count was unavailable in one case.
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Lindhardt Johansen et al.
45,X/46,XY: Phenotype, Puberty, and Growth
J Clin Endocrinol Metab, August 2012, 97(8):E1540 –E1549
TABLE 1. Continued
IMS
Diagnosis
Fallopian
tube (R/L)
Epididymis
(R/L)
3
—
—
—
—
3
—
3
0
3
—
—
2
—
—
—
—
2
—
0
0
2
—
—
2
—
—
—
—
2
—
0
0
2
—
—
—
—
—
—
—
—
—
—
0
—
2
—
—
—
—
—
—
—
—
—
0
—
—
—
—
—
—
—
—
—
—
0
0
2
—
—
—
—
—
—
—
—
—
2
0
2
—
—
Prenatally
Prenatally
Prenatally
Prenatally
Prenatally
At birth
At birth
At birth
At birth
At birth
10
11
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
17
22
28
33
47
49
Uterus
Vas
deferens (R/L)
Age (yr)
At last follow-up
Reason
for referral
Age
(yr)
Fetal factorsa
Maternal age
Fetal factorsb
—
Maternal request
Abnormal genitals
Abnormal genitals
Abnormal genitals
Abnormal genitals
Abnormal genitals
Growth retardation
Growth retardation,
delayed puberty
Growth retardation
Lack of virilization
Infertility
Infertility
Infertility
Infertility
2
3
4
7
8
0
6
14
14
22
15
20
pp
2
2
1
2
pp
pp
NA
NA
NA
20
15
18
38
47
34
48
53
10
15
0
6
18
4
Spontaneous
puberty
Turner stigmata, renal,
cardiac, otitis media,
hypothyroid
pp
2
2
1
2
pp
pp
6
3
7
pp
12
⬍9 yr
⬍9 yr
⬍9 yr
⬍9 yr
⬍9 yr
⬍9 yr
⬍9 yr
Yes
No
Yes
Yes
Yes
No
No
No
No
No
Renal
Renal, cardiac, otitis
No
Cardiac
No
No
No
12
12
2
12
12
4
Yes
Yes
Yes
Yes
Yes
Yes
Tvol
(ml) (R/L)
No
No
No
No
No
No
Deletion analysis of the Y chromosome
Controls
A microdeletion analysis of the Y chromosome was performed in six patients using DNA samples purified from white
cells of peripheral blood. The method, a previously described
multiplex PCR (9), screened for the presence of 12 gene-specific
sequences or sequence-tagged site markers spanning the azoospermia factor (AZF) region on the Yq arm as well as SRY and
ZFY/ZFX loci on Yp and Yp/Xp, respectively. Anonymous samples from a normal 46,XY male and a normal 46,XX female,
served as positive and negative controls, respectively.
A total of 1823 healthy girls and 2095 healthy boys recruited
for a cross-sectional study of healthy, Danish children (The Copenhagen Puberty Study) participated as controls for reproductive hormones and growth factors, as previously described by
others (14 –19). Heights were compared with the national
growth reference (20).
Clinical examination
We measured heights on a wall-mounted stadiometer
(Harpenden, Holtain Ltd., Crymych, United Kingdom). Height
at last evaluation before GH treatment or in adulthood was expressed as height SD scores (SDS) before and after correction for
target height (target height SDS ⫺ actual height SDS). Target
height was calculated as the mean of maternal and paternal
height SD, which were then back-transformed to sex-specific
heights (in centimeters) without correction for secular trend.
Birth weight and height were evaluated and compared with a
reference for gestational age, as previously described by Niklasson et al. (10). We determined the pubertal staging of the boys
using Tanner’s classification (11) and testicular volume by Prader’s orchidometer (12). Spontaneous pubertal onset was defined
as a testicular volume greater than 3 ml. Boys below the age of
9 yr were categorized as being too young to be evaluated for the
presence of spontaneous puberty. If puberty had not begun by the
age of 14, we recorded it as lack of spontaneous puberty. Patients
were scored using the external and internal masculinization
scores (EMS and IMS) as described by Ahmed et al. (13).
Hormone assays
Blood was drawn from an antecubital vein. The samples were
then centrifuged and stored at ⫺20 C. We analyzed all blood
samples in the same laboratory blinded for the technician for age
and pubertal staging. Serum FSH and LH were determined using
the time-resolved immunofluorometric assays (Delfia; PerkinElmer, Boston, MA). The detection limits were 0.06 and 0.05 IU/
liter, respectively, with intra- and interassay coefficients of variation (CV) of less than 5% in both assays. Using RIA (after 1998,
Pantex, Santa Monica, CA; before 1998, Immunodiagnostic Systems, Bolton, UK), we measured the estradiol serum levels with
a detection limit of 18 pmol/liter and intra- and interassay CV of
less than 8 and 13%, respectively. Testosterone concentrations
were determined using RIA (DPC Coat-A-Count; Diagnostic
Products Corp., Los Angeles, CA) with a detection limit of 0.23
nmol/liter. Intra- and interassay CV were less than 17%. We
measured inhibin B levels using a double antibody immunometric assay (Serotec, Oxford, UK) with a detection limit of 20 pg/ml
and intra- and interassay CV of less than 16%. Serum IGF-I and
IGF binding protein-3 were determined using RIA as previously
described (17, 21). For IGF-I, the detection level was 20 ng/ml,
and the intra- and interassay CV were less than 6 and 15%,
respectively. IGF-I age-related z-scores were calculated as described by Juul et al. (17). For IGF binding protein-3, the detec-
J Clin Endocrinol Metab, August 2012, 97(8):E1540 –E1549
jcem.endojournals.org
E1543
TABLE 2. EMS and IMS of phenotypically predominantly female patients
EMS
Patient no.
19
20
21
22
23
24
25
Sex
F
F
F
F
F
F
F
Karyotype
45,X关3兴/46,XY关7兴
45,X关55兴/46,XY关6兴
45,X关30兴/46,XY关11兴
45,X关7兴/46,Xdic(Y)(q12)关22兴
45,X关8兴/46,Xidic(Y)(q11)关22兴
45,X关10兴/45,Xt(Y;22)(q12;p11)关102兴
45,X关2兴/46,XY关28兴
Scrotal
fusion
3
3
0
0
0
0
0
Micro
penis
0
3
3
0
3
0
0
Urethral
meatus
0
0
0
0
0
0
0
Right
gonad
0.5
0.5
1
0.5
0.5
0.5
0.5
Left
gonad
0.5
1
1
0.5
1
0.5
0.5
Total
EMS
4
7.5
5
1
4.5
1
1
EMS and IMS data are as described by Ahmed et al. (13). Scores (yes/no or gradient): scrotal fusion (3/0); micropenis (0/3); urethral meatus
(normal, 3; glandular, 2; penile, 1; perineal, 0); right and left gonad (scrotal, 1.5; inguinal, 1; abdominal, 0.5; absent, 0); uterus (0/3); right and left
fallopian tube (0/2); right and left epididymis (2/0); right and left vas deferens (2/0). F, Female; R/L, right/left; NA, not applicable due to
gonadectomy; —, information not available in patient file.
tion level was 400 ng/ml, and the intra- and interassay CV were
less than 6 and 9%, respectively.
of the Y chromosome, and one patient had translocation
between the Y chromosome and chromosome 22.
Histological evaluation
Age at diagnosis
Six patients (five boys) were diagnosed prenatally: two
boys due to fetal factors (increased nuchal fold or positive
triple diagnostics: abnormal levels of serum ␣-fetoprotein,
human chorionic gonadotropin, and/or unconjugated estradiol), and two boys and one girl due to maternal age or
request. Seven patients (five boys) were diagnosed at birth
due to genital malformations, and six patients (two boys)
between ages 4 and 17 due to short stature or the combination of short stature and delayed puberty (one boy). Five
male patients were diagnosed in adulthood due to infertility (n ⫽ 4) and lack of virilization (n ⫽ 1).
Tissue samples were fixed in buffered formalin (gonadectomies)
or in modified Stieve’s fluid (biopsies) and paraffin-embedded. Pathologists performed histological evaluations on hematoxylin-eosin-stained sections with the aid of immunohistochemical staining
for placental-like alkaline phosphatase (PLAP; Dako, Glostrup,
Denmark) and, in most cases, OCT4 (Santa Cruz Biotechnology,
Santa Cruz, CA). We performed immunohistochemical staining for
additional markers of germ cell and Sertoli-cell maturation on specimens from six patients where tissue blocks were available. The
following antibodies were used: c-KIT (Dako), podoplanin (D2-40;
Dako), AP-2␥ (Santa Cruz Biotechnology), and anti-Müllerian hormone (a gift from Dr. R. L. Cate, Department of Biological Research, Biogen, Cambridge, MA). Immunohistochemistry was
done using a standard indirect peroxidase method with reagents
and secondary antibodies from Zymed and Dako, as previously
described (22–24). We used specimens of an adult testis with carcinoma in situ (CIS) pattern and a normal juvenile testis as positive
controls for the markers used. For negative controls, the dilution
buffer substituted the primary antibodies. The stained sections were
scanned (Nanozoomer; Hamamatsu, Hamamatsu City, Japan) and
evaluated by three investigators (N.E.S., E.R.-D.M., B.L.P.), who
also reevaluated all initial preparations and pathology reports.
Ethical considerations
Blood and tissue samples were taken as part of the clinical
follow-up on the patients. The study of the controls (The
Copenhagen Puberty Study, www.ClinicalTrials.gov, ID:
NCT01411527) was approved by the local ethical committee
(no. KF 01 282214 and no. V200.1996/90) and the Danish
Data Protection Agency (2010-41-5042). All controls and
parents gave informed consent.
Phenotype at birth
Fourteen of 18 male patients had EMS of 11.5–12 out
of 12 maximum points at the initial examination (Table 1).
The lowest scoring male had an EMS of 1 and an IMS of
0. The EMS of the females varied between 3 and 7.5, thus
ranking some of the girls as more masculinized than the
lowest scoring boys (Table 2). Two patients were small for
gestational age (patients 8 and 11).
Results
Reproductive hormones and puberty in males
Ten of 11 male patients experienced spontaneous pubertal onset. As seen in Fig. 1, five of them had hormonal
data available during and after the time of expected puberty. Prenatally diagnosed boys demonstrated normal
phenotype at birth and normal reproductive hormones in
minipuberty. The oldest of these boys was, however, only
8 yr old at the last evaluation.
Karyotype
Eight of 25 patients (three girls, five boys) had variants
of the 45,X/46,XY karyotype. Five patients had isodicentricism of the Y chromosome, two patients had deletions
Postnatal growth
As seen in Fig. 2, A and B, all patients were short, but
the prenatally diagnosed were generally taller. Height SDS
was ⫺2.0 (⫺3 to 0.3) [median (range)] for the boys and
E1544
Lindhardt Johansen et al.
45,X/46,XY: Phenotype, Puberty, and Growth
J Clin Endocrinol Metab, August 2012, 97(8):E1540 –E1549
TABLE 2. Continued
IMS
Fallopian Epididymis
Vas
Uterus tube (R/L)
(R/L)
deferens (R/L)
0
2
2
0
0
0
0
0
—
—
—
—
—
—
0
0
0
—
—
—
—
0
0
0
0
0
0
0
0
0
0
—
—
—
—
0
—
—
—
—
—
—
0
—
—
—
—
—
—
Diagnosis
At last follow-up
Turner stigmata,
Reason
Age Spontaneous renal, cardiac, otitis
Age (yr)
for referral
(yr)
puberty
media, hypothyroid
Prenatally Maternal age
12
NA
No
At birth
Abnormal genitals
2
NA
No
At birth
Abnormal genitals
26
NA
No
2
—
22
NA
Renal, cardiac
4
Growth retardation
9
NA
No
6
Growth retardation 13
NA
Otitis
15
Growth retardation 32
No
Otitis, hypothyroid
⫺2.2 (⫺2.5 to ⫺1.4) for the girls. Height SDS corrected
for target height was ⫺2.6 (⫺3.6 to ⫺0.5) for the boys and
⫺1.8 (⫺3.1 to ⫺0.4) for the girls.
IGF-I levels
IGF-I levels were within the normal ranges, although
most values were below the age-related mean (Fig. 2, C
and D).
GH treatment
Seven patients (three boys, four girls) received GH
treatment. The effects of treatment on height and IGF-I
are seen in Supplemental Fig. 1 (published on The Endocrine Society’s Journals Online web site at http://
jcem.endojournals.org). After 1 yr of treatment, all
seven patients had increased height [0.51 (0.1–1.2)]
[median ⌬SDS (range)] and increasing IGF-I [2.25
(1.3–2.39)].
Histological findings
Histological findings are summarized in Table 3, and
representative histological images are shown in Fig. 3
and Supplemental Fig. 2. No sample revealed normal
gonadal histology. In three of six males, we observed
poorly developed dysgenetic gonads. In the males with
well-developed testicular architecture, Sertoli cell-only
(SCO) pattern and/or Leydig cell hyperplasia were often
present (n ⫽ 5). Two males had testicular microlithiasis.
In females, streak gonads or poorly developed ovarian
structures were common. Two females had testis-like
tubular structures.
Two males and one female had verified histological
findings consistent with the presence of CIS, confirmed by
positive reactions with PLAP, and/or OCT4, cKIT, and
M2A/D2-40. In one boy (patient 8; Tables 1 and 3 and Fig.
3, E and F) with ambiguous genitalia (EMS ⫽ 4), bilateral
surgical exploration revealed a streak gonad with ovarianlike stromal tissue on one side (which was removed) and
a dysgenetic testis without signs of malignancy on the
other side. Due to ultrasonic microlithiasis, this testis was
rebiopsied at the age of 14 yr (Fig. 3F). In another boy with
ambiguous genitalia (patient 9; Tables 1 and 3 and Fig. 3,
A and D), CIS cells were detected in a right-sided testicular
biopsy performed at the age of 2 (Fig. 3, A and B) simultaneously with the removal of the rudimentary gonad and
Müllerian-like structures on the left side. In this boy, the
left testis was removed at the age of 14 yr due to severe
microlithiasis at ultrasound, lack of spontaneous puberty,
and poor testis growth combined with a high risk of an
invasive tumor (Fig. 3, C and D). In both patients, histological analysis revealed the presence of a widespread pre-/
peripubertal CIS pattern, confirmed by PLAP, OCT4, AP2␥, and M2A/D2-40 positivity, and in patient 9 also
revealed clusters of distorted dysgenetic tubules with
poorly differentiated Sertoli cells. Patient 8 had a few tubules with late spermatids, suggesting the onset of puberty, which was consistent with the clinical observation
of early spontaneous pubertal onset.
In one female diagnosed due to growth retardation (patient 23; Table 2 and Fig. 3G), we found a dysgenetic
infantile testis with widespread CIS (confirmed by immunohistochemical markers), and a contralateral streak gonad devoid of germ cells was present (Fig. 3G).
We have summarized all above clinical findings in Supplemental Table 1, in which management strategies and
considerations for patients with 45,X/46,XY mosaicism
and its variants are listed.
Discussion
To our knowledge, this is the most comprehensive evaluation of patients with 45,X/46,XY mosaicism and its
variants because it demonstrates the broad spectrum of
cytogenetic, clinical, biochemical, and histological characteristics. Interestingly, gonadal function in male patients
J Clin Endocrinol Metab, August 2012, 97(8):E1540 –E1549
jcem.endojournals.org
E1545
case of males with a very low EMS. Ten
male patients with scores of 4 or higher
entered puberty spontaneously, and
only one patient with the EMS of 1 did
not. The most noteworthy part of this
observation is that even male patients
with rather ambiguous genitalia have a
good chance of Leydig cell function and
thus spontaneous puberty. This supports previous findings of frequent
spontaneous puberty in 45,X/46,XY
males (6, 7). In a recent review of 45,X/
46,XY males with ambiguous genitalia, it was, conversely, noted that some
patients needed HRT after spontaneous pubertal onset (7). As previously
discussed, most 45,X/46,XY patients
are, however, born as normally virilized males, and we have not seen a single case of the need for testosterone
treatment after spontaneous pubertal
onset in our patients. Thus, it seems
that a normal male genital phenotype at
birth is a good predictor of sufficient
testicular function to allow for full puberty, whereas males born with ambiguous genitalia may enter puberty spontaneously but subsequently need HRT.
All males with hormone values available during and after puberty had low
testosterone levels. We found no distinct
difference between the hormone levels of
the male that did not experience puberty
and those that did. Our data set is, however, small and thus limits the conclusions that could be drawn. The only male
patient without spontaneous puberty
had elevated gonadotropin levels at the
time of and after expected puberty,
FIG. 1. Reproductive hormones in male patients with 45,X/46,XY mosaicism and its variants.
whereas mid-childhood levels were
Serum levels of LH, FSH, testosterone, estradiol, and inhibin B according to age in male
within the reference range, which suppatients with a 45,X/46,XY karyotype. Green color represents values of prenatally diagnosed,
ports previous findings in patients with
blue color represents postnatally diagnosed. Black lines represent normal ranges (mean ⫾ 2
SD) as previously reported (15, 16, 18, 19).
gonadal failure (25, 26).
The practice of gonadectomy at an
seems sufficient to allow for spontaneous pubertal onset.
early age prevents the further study of the female gonadal
The karyotype appears to be incompatible with normal
function. Based on previous studies, it must, however, be
gonadal histology. Furthermore, the patients were short,
assumed that it is impaired because their female cell line,
but they seem to benefit from GH treatment.
Based on the high prevalence of male spontaneous pu- 45,X, is rarely compatible with normal gonadal function
berty in this study, phenotypical males with a 45,X/46,XY (25). The presence of bi- or unilateral streak gonads in the
karyotype and its variants seem to have a strong chance of majority of females in our series supports this assumption.
testicular function. It appears that EMS can mostly be used It is, however, striking that in two of seven patients raised
as an indicator of clinically malfunctioning gonads in the as girls because of a low EMS, testicular tissue was present,
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A
Lindhardt Johansen et al.
45,X/46,XY: Phenotype, Puberty, and Growth
B
J Clin Endocrinol Metab, August 2012, 97(8):E1540 –E1549
cases of CIS in 25 patients, our data set
is too small to add further knowledge.
180
160
However, in a larger series (n ⫽ 48),
160
gonadal malignancy risk in males
140
seemed to be greatest in individuals
140
120
with the most pronounced sexual am120
biguity (6). The low EMS of 4 and 1,
100
100
respectively, in our two male patients
80
with CIS and the high EMS of 4.5 in the
80
female patient with CIS further support
60
60
this theory.
Interestingly, our histological find40
40
0
5
10
15
0
5
10
15
ings
in patient 8 revealed a typical CIS
Age (years)
Age (years)
pattern alongside a few tubules with
C
D
ongoing complete spermatogenesis in a
1000
1000
biopsy performed in adolescence, despite the absence of gonocytes or CISlike cells in a biopsy performed at 1 yr
of age. In patient 9, who had exploratory surgery and a unilateral gonad100
100
ectomy at 2 yr of age, histological evaluation of the biopsies revealed the
presence of large gonocytes, retaining a
high expression of PLAP that should be
10
10
absent at that age (31). The cells were
0
5
10
15
20
0
5
10
15
20
classified as possible early CIS cells, but
Age (years)
Age (years)
the testis was left in place to allow for
FIG. 2. Growth and IGF-I levels in patients with 45,X/46,XY mosaicism and its variants. A,
further virilization (the contralateral
Growth according to age in male patients with a 45,X/46,XY karyotype. Green color
represents values of prenatally diagnosed, blue color represents postnatally diagnosed. Black
streak gonad was removed). A control
lines represent the national growth reference (20). B, Growth according to age in female
ultrasound showed signs of microlithipatients with a 45,X/46,XY karyotype. Green color represents values of prenatally diagnosed,
asis, prompting a decision of orchiecred color represents postnatally diagnosed. Black lines represent the national growth
tomy at the age of 14. A widespread,
reference (20). C, Serum levels of IGF-I according to age in male patients with a 45,X/46,XY
karyotype. Green color represents prenatally diagnosed patients, blue color represents
typical CIS pattern was found. These
postnatally diagnosed. Black lines represent normal ranges (mean ⫾ 2 SD) as previously
two cases are some of the very first dereported (17). D, Serum levels of IGF- I according to age in female patients with a 45,X/46,XY
scriptions of pre- or peripubertal CIS
karyotype. Green color represents prenatally diagnosed patients, red color represents
postnatally diagnosed. Black lines represent normal ranges (mean ⫾ 2 SD) as previously
and add evidence to our long-standing
reported (17).
hypothesis that this malignancy originates before, not after, puberty. Furand in one the presence of CIS was verified. An important
thermore, the cases add a note of caution concerning the
implication of this observation is that a low degree of
sensitivity of testicular biopsies performed in early
masculinization at birth in females with 45,X/46,XY moinfancy.
saicism does not seem to exclude the possibility of testis
Eight of 25 patients had variants of the 45,X/46,XY
tissue with CIS. Furthermore, based on the findings in five
karyotype
with aberrations of their Y chromosome. Intuof 25 patients (20%), it is not exceptional to see a testis and
a contralateral streak gonad or ovarian-like stromal tissue, itively, one would expect abnormalities of the Y chromoin line with a variable distribution of the Y chromosome- some to lead to a more feminine phenotype and gonadal
containing line (27). It also adds further strength to the histology. However, we did not find this. Four of five
theory that CIS is associated with a masculinization of the males had EMS of 12; they were fully virilized, and one of
gonad, whereas gonadoblastoma is primarily seen in ovar- three females had an EMS of 4.5, making her rather virilized. Gonadal histology did not differ from that of paian-like structures (28, 29).
Previously, the risk of gonadal malignancy in individ- tients with a 45,X/46,XY karyotype. There are obviously
uals with 45,X/46,XY mosaicism and its variants has been limits to this conclusion because it is based on merely eight
described to be 10 –15% (7, 30). With three confirmed patients.
Height (cm)
Height (cm)
IGF-I (ng/ml)
IGF-I (ng/ml)
200
180
J Clin Endocrinol Metab, August 2012, 97(8):E1540 –E1549
jcem.endojournals.org
E1547
TABLE 3. Histological findings in patients who underwent surgical exploration and/or gonadectomy
Histology
Patient
no.
Sex
8
M
9
10
Karyotype; deletion
Surgery
Left gonad
Right gonad
45,X关182兴/46,XY关34兴
At 1 yr, B (left), G
(right)
At 14 yr, G (left)
Streak gonad with some ovarian-like
stromal tissue, no germ cells
M
45,X关80兴/46,XY关20兴
At 2 yr, G (left), B
(right)
At 14 yr, G (right)
Dysgenetic testis, sp-gonia present, Leydig
cells absent, microlithiasis
Testis with some sp-gonia, widespread
CIS, microlithiasis, and Leydig cell
hyperplasia
Streak gonad with a few tubules with
atypical gonocytes, rudimentary uterus
M
45,X关8兴/46,XdefY关2兴
At 14 yr, G (right),
B (left)
At 21 yr, B (left)
11
M
45,X关17兴/46,XY关30兴; no deletions
At 10 yr, O (right)
12
M
15
M
45,X关22兴/46,X del(Y)(q12)关13兴;
AZF b⫹c
45,X关20兴/46,XY关80兴; no deletions
At 19 yr, B
(bilateral)
At 22 yr, O (right)
At 38 yr, B (left)
At 34 yr, B
(bilateral)
At 49 yr, B
(bilateral)
Connective tissue only
Dysgenetic infantile testis, atypical
gonocytes with CIS characteristics
Prepubertal testis, focally dysgenetic
SCO tubules, widespread CIS
Rudimentary uterus with tuba
uterina and ovary, no germ cells
Testis with predominantly SCO, few SPA
tubules, Leydig cell hyperplasia
Testis with SCO, Leydig cell hyperplasia
Atrophic testis, hyalinization, SCO,
microlithiasis, Leydig cell hyperplasia
Testis with hyalinized tubules, SPA, SCO,
interstitial fibrosis
Testis with SPA, Leydig cell hyperplasia
16
M
45,X关30兴/46,XY关24兴; AZF b⫹c
18
M
45,X关10兴/46,X idic(Y)(p)关20兴; AZF
a⫹b⫹c
19
F
45,X关3兴/46,XY关7兴
At 1 yr, G
(bilateral)
Streak gonad, single germ cells present
20
F
45,X关55兴/46,XY关6兴
At 4 months, G
(bilateral)
Streak gonad, no germ cells
21
F
45,X关30兴/46,XY关11兴
22
F
45,X关7兴/46,Xdic(Y)(q12)关22兴
Reported as streak gonad
(not verified)
Streak gonad, no germ cells
23
F
45,X关8兴/46,Xidic(Y)(q11)关22兴; no
deletions
At 5 months, G
(bilateral)
At 5 yr, G
(bilateral)
At 4 yr, G
(bilateral)
24
F
25
F
45,X关10兴/45,Xt(Y;22)(q12;p11)关102兴 At 8 yr, G
(bilateral)
45,X关2兴/46,XY关28兴
At 17 yr, G
(bilateral)
Rudimentary uterus, bilateral tubae
and a small rudimentary
ovotesticular remnant with
tubules devoid of germ cells
Testis with SCO, Leydig cell
hyperplasia
Necrotic testis after infarction
Testis with SCO, single tubule with
poorly differentiated Sertoli cells
Testis with SPA, abnormal sp-gonia,
many SCO tubules, hyalinization,
Leydig cell hyperplasia
Dysgenetic ovary, locally tubule-like
structures, a few germ cells
present
Dysgenetic testis with streak-like
areas, gonocytes and infantile
sp-gonia present
Reported as streak gonad, CIS
(not verified)
Streak gonad, no germ cells
Dysgenetic infantile testis with distorted
tubules, some sp-gonia, and
widespread CIS
Atrophic ovary, no germ cells
Streak gonad, no germ cells
Atrophic ovary, no germ cells
Streak gonad
Streak gonad
Patient numbers are the same as in Tables 1 and 2. M, Male; F, female; B, biopsy; G, gonadectomy; O, orchiopexy; sp-gonia, spermatogonia; SPA,
spermatocytic arrest; no deletions, no microdeletions on the Yq in the AZFa, AZFb, AZFc region along with SRY and ZFY/ZFX.
Oligo- and azoospermia have been shown to be
caused by chromosomal abnormalities including
changes in the Y chromosome (5, 32). It is interesting
that three of four males presenting with infertility had
additional structural abnormalities of the Y chromosome that removed a large fragment of the q arm comprising the AZF region, which harbors numerous genes
involved in spermatogenesis (7, 33). The absence of this
region causes a severe depletion or absence of germinal
epithelium and consequently often leads to SCO and
progressive hyalinization of tubules (34), thus markedly
worsening the testicular phenotype caused by the sex
chromosome mosaicism.
The prevalence of growth retardation in our patients
was high, especially when compared with their genetic
potential. All patients, however, had normal IGF-I values.
An association between the 45,X/46,XY karyotype and its
variants and growth retardation is therefore highly likely,
as also described previously (2, 5, 7), although it does not
seem to be due to GH deficiency. Further investigation
should be focused on factors affecting growth in these
patients, like SHOX haploinsufficiency (35, 36). The patients subjected to GH treatment in this study benefited in
terms of increasing height, which is in accordance with
another recent uncontrolled study (8). The results of Martinerie et al. (7) did not, however, show any significant
height improvements after GH treatment. This calls for
the need of a randomized study of the effect, or lack
thereof, of GH treatment in this unique group of patients.
Nonetheless, we do recommend for now that if short stature is present in patients with a 45,X/46,XY karyotype,
GH treatment be considered.
E1548
Lindhardt Johansen et al.
45,X/46,XY: Phenotype, Puberty, and Growth
A
25 μm
B
25 μm
D
C
100 μm
100 μm
E
100 μm
F
200 μm
G
J Clin Endocrinol Metab, August 2012, 97(8):E1540 –E1549
As previously presented by Chang et al. (37), it is expected
that 95% of prenatally diagnosed cases will be born as phenotypically normal males (6, 37). Five of six of our prenatally
diagnosed patients were boys with EMS of 12, thus supporting these findings (6, 37). The indication for amniocentesis in
these prenatally diagnosed patients must, however, be considered. For two of five patients with a known indication, it
was fetal factors in terms of increased nuchal fold or anomalous triple screening (abnormal levels of serum ␣-fetoprotein, human chorionic gonadotropin, and/or unconjugated
estradiol). Because both of these patients had EMS of 12, it
could indicate that the chance of a normal male phenotype is
high despite fetal risk factors.
In conclusion, this paper adds to the existing knowledge
of how to best clinically manage patients with 45,X/46,XY
mosaicism and its variants. The clinician must bear in mind
that the phenotypes of the patients vary greatly, and EMS
does not always reflect the true masculinization of the gonad
and the risk of CIS. The chance of phenotypically predominant male patients entering puberty is high, although their
fertility potential is uncertain. The 45,X/46,XY karyotype
and its variants are associated with growth retardation, and
the patients appear to respond well to GH treatment. Treating each patient individually is the most important step in the
clinical management (38, 39).
Acknowledgments
100 μm
FIG. 3. Gonadal histology in three patients with CIS testis and
45,X/46,XY mosaicism and its variants. Patient numbers are the same as in
Tables 1 and 2. A and B, Patient 9 at the age of 2 (A, PAS-stained; B, KITstained). Germ cells considered as CIS-like cells are marked by arrows.
Note that only one cell near the lumen is positive for KIT. C and D, The
same boy at 14 yr, when the gonad was removed due to florid
microlithiasis (C, hematoxylin-eosin-stained; D, PLAP-positive CIS cells). E,
A dysgenetic testis in patient 8 at 13 months (left-sided gonad) with
normal appearing germ cells, which are positive for a spermatogonial
marker MAGEA4 (inset). F, The testis from the same boy (patient 8) at the
age of 14 when he was diagnosed with CIS at the rebiopsy. Inset shows
OCT4-positive CIS cells. G, A 4-yr-old female (patient 23) with a streak
gonad on the right side and, shown here, a dysgenetic left testis with a
CIS-like pattern; the inset shows a tubule with PLAP-positive CIS cells.
It is important to note the ascertainment bias in our
study that includes prenatally diagnosed cases, children
with sexual ambiguity and/or growth problems, and infertile men, thus covering all phenotypic presentations of
this patient population. Furthermore, we have only seen
patients who sought medical care. This creates an inherent
bias present in all postnatal studies of patients with 45,X/
46,XY mosaicism thus far. It is therefore impossible to
make statements applicable to all 45,X/46,XY patients,
and clinicians must bear this in mind. Management should
thus be individualized for each patient.
Address all correspondence and requests for reprints to: Anders
Juul, Department of Growth and Reproduction, GR, Rigshospitalet, Blegdamsvej 9, DK-2100 København Ø, Denmark.
E-mail: [email protected].
Disclosure Summary: M.L.J., C.P.H., E.R.-D.M., S.K.,
B.L.P., N.E.S., and K.M.M. have nothing to declare. A.J. received a research grant from Novo Nordisk and lecture fees from
Novo Nordisk, Pfizer, and Ferring.
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