J Gynecol Obstet Hum Reprod 50 (2021) 102228

Contents lists available at ScienceDirect

Journal of Gynecology Obstetrics

and Human Reproduction
journal homepage: www.elsevier.com

Review

Adenomyosis: An update regarding its diagnosis and clinical features

Maignienb,
Mathilde Bourdona,b,c,Ϯ,*, Pietro Santullia,b,c,Ϯ, Louis Marcellina,b,c, Chloe
b d
Lorraine Maitrot-Mantelet , Corinne Bordonne , Genevie ve Plu Bureaua,b,
a,b,c
Charles Chapron
a
Universite
de Paris, Faculte
de me
decine, Paris, France
b
De
partement de Gyne
cologie Obste
trique II et me
decine de la reproduction, Ho^pital Cochin (UHC), Assistance Publique−Ho ^pitaux de Paris (AP−HP), Ho ^pital uni-
versitaire Paris Centre (HUPC), Paris, France
c
De
partement 3I “Infection, Immunite
et inflammation”, Cochin Institute, INSERM U1016, Paris, France
d
De
partement de radiologie, Ho ^pital Ho
^tel Dieu, Assistance Publique−Ho
^pitaux de Paris (AP−HP), Ho^pital universitaire Paris Centre (HUPC), Paris, France

A R T I C L E I N F O A B S T R A C T

Article History: Adenomyosis is a common gynecologic disease characterized by invasion of endometrial glands and stroma
Received 2 April 2021 within the myometrium. Clinically, it can result in abnormal uterine bleeding, pelvic pain, and infertility.
Revised 29 July 2021 Adenomyosis has historically been diagnosed by histology of hysterectomy specimens. As a result of the
Accepted 8 September 2021
development of imaging techniques, the diagnosis is nowadays possible by means of transvaginal pelvic
Available online 11 September 2021
ultrasound or pelvic magnetic resonance imaging. The use of pelvic imaging has demonstrated the existence
of different forms of adenomyosis, notably allowing distinction between lesions of the external myometrium
Keywords:
and those of the internal myometrium. The epidemiological and clinical characteristics may depend on the
Adenomyosis
Myometrium
anatomical location of the adenomyosis lesions. In order to provide the best management for women with
Endometrium adenomyosis, the objective of this review is to provide an update regarding the diagnosis of adenomyosis
Clinical and its clinical features according to the different adenomyosis phenotypes.
Diagnosis © 2021 Elsevier Masson SAS. All rights reserved.

Introduction phenotypes could correspond to different forms of the disease,

with different pathophysiological mechanisms, risk factors, and
Adenomyosis is a common pathology in women of reproduc- clinical profiles according to the localization of the lesions in the
tive age that is characterized by infiltration of the myometrium internal and/or the external myometrium [7−9]. The objective of
by endometrial tissue, composed of glands and stroma [1]. At the this work is to provide an update regarding the diagnosis of
clinical level, adenomyosis can result in abnormal uterine bleed- adenomyosis and its clinical symptoms, particularly according to
ing, pelvic pain, and/or infertility [2]. Until recently, the diagnosis the different phenotypes of adenomyosis.
of adenomyosis could only be made retrospectively by means of a
histological examination of the uterus, after a hysterectomy, in
Sources
symptomatic women who no longer had a desire to become preg-
nant. With the development of imaging techniques such as trans-
A PubMed search of the literature from 1950 to March 2021
vaginal pelvic ultrasound (TVUS) and magnetic resonance
was performed in order to summarize all of the diagnostic crite-
imaging (MRI), adenomyosis can now also be diagnosed without
ria and clinical presentations of adenomyosis. All pertinent
surgical intervention [3]. This allows the diagnosis to also be
articles were examined and their reference lists were reviewed
made in young women, with or without clinical symptoms. Fur-
in order to identify other studies for potential inclusion. The lit-
thermore, different anatomical locations of adenomyosis lesions
erature search included the following terms: ‘adenomyosis’,
have been shown to occur within the myometrium (particularly
‘pain’, ‘abnormal uterine bleeding’, ‘heavy menstrual bleeding’,
in its internal and/or external part) [4−6]. These adenomyosis
‘infertility’, ‘dysmenorrhea’, ‘dyspareunia’, ‘diagnosis’, ‘histopa-
thology’, ‘junctional zone’, ‘MRI’, ‘myometrium’, ‘transvaginal
ultrasonography’, ‘ultrasound’. Only peer-reviewed journal
* Corresponding author at: Division of Reproductive Medecine and Infertility,
Department of Obstetrics and Gynecology II, Universite
de Paris − Ho ^ pital Cochin − articles were included.
Batiment Port Royal, 53 avenue de l'Observatoire 75679 Paris 14, France.
E-mail address: mathilde.bourdon@aphp.fr (M. Bourdon).
Ϯ The authors consider that the two first authors should be regarded as joint first
authors.

https://doi.org/10.1016/j.jogoh.2021.102228
2468-7847/© 2021 Elsevier Masson SAS. All rights reserved.
M. Bourdon, P. Santulli, L. Marcellin et al.
Epidemiology
Prevalence
The prevalence of adenomyosis is hard to estimate given the exis-
tence of asymptomatic forms and different diagnostic modalities (his-
tological or by imaging). Estimation of the prevalence, based on series
of patients treated by hysterectomy, is on the order of 20−30%, but
there is a substantial degree of variation in this estimation, ranging
from 5 to 70% [10]. The prevalence of adenomyosis in series where
the diagnosis was based on imaging is approximately 20−30% [6,11].
In a large study of an American cohort involving more than 300 000
women, the prevalence also appeared to depend on age, with 20.7%
of cases found in those aged 36−40 years [12]. Thus, these data con-
firm the high frequency of this disease in women of reproductive age.
The main risk factors
Prior pregnancies, uterine surgery, and the age of the women
Several authors have observed that adenomyosis, when diagnosed
during a hysterectomy, was directly associated with the number of
births and had a tendency to be more frequent in case of miscarriages
or voluntary pregnancy terminations [13,14]. Similarly, prior uterine
surgery, such as a cesarean, appears to increase the risk of adenomyo-
sis [14,15].
Increased age as a risk factor for the disease has also been demon-
strated [12,16,17], although the majority of the currently available
epidemiological studies are often carried out with a population that
has been treated by hysterectomy and that is hence possible older. A
recent study, for which the diagnosis of adenomyosis was based on
ultrasound, carried out in women aged 18 to 30 years, found that
more than 30% of young women exhibited characteristics of adeno-
myosis [11]. Similarly, a study in which the diagnosis of adenomyosis
was based on MRI, in women less than 42 years of age found that
adenomyosis was present in 59.9% of the population of the study [6].
Thus, adenomyosis is a pathology that can also occur in women at
the start of reproductive age. Contrary to what was thought a few
years ago, adenomyosis can be found in young women without any
risk factors such as history of pregnancy or uterine surgery.
Endometriosis
Adenomyosis and endometriosis are two gynecological patholo-
gies that often coexist [18]. However, the prevalence of adenomyosis
in association with endometriosis is variable in the literature. For
some authors, the prevalence of adenomyosis in endometriotic
patients is 80−90% [19]. Other studies have found adenomyosis in
less than half of the patients exhibiting endometriosis [17], or even
an absence of a relationship between adenomyosis and endometri-
osis [14]. According to Kishi et al. and Chapron et al., Endometriosis is
found in more than 90% of patients presenting adenomyosis of the
external myometrium. The authors demonstrated a difference in
endometriosis prevalence according to the location of the adenomyo-
sis lesion in the myometrium [5,6].
Diagnosis
Anatomopathological analysis
A clear diagnosis of adenomyosis is based on the presence of
ectopic endometrial tissue in the myometrium by anatomopathologi-
cal analysis [20].
Macroscopic presentation
With advanced adenomyosis, the uterine body is generally
enlarged, or even globular in the more extreme forms. The enlarge-
ment can be diffuse, predominantly in the uterine wall, generally the
2
Journal of Gynecology Obstetrics and Human Reproduction 50 (2021) 102228
posterior wall [20], or it can be focalized, which leads to the forma-
tion of intramural nodules. This enlargement is mainly the conse-
quence of hyperplasia/hypertrophy of the smooth muscle that
accompanies the sites of the adenomyosis. Small glandular cysts are
frequently observed in the youngest patients [21].
Microscopic presentation
There is not a consensus to define robust clinical criteria for
microscopic diagnosis of adenomyosis. The ectopic endometrial tis-
sue presents as variably sized entities situated in the myometrium
[20]. The ectopic endometrium has to be observed at least 2.5 mm
from the interface between the endometrium and the myometrium
[10], but the limiting values proposed in the literature are variable,
ranging from 2 mm to 1/3 of the wall of the uterus [3]. The hyperpla-
sia/hypertrophy of the smooth muscle is visible as nodules around
the ectopic sites of the endometrium. These nodules generally exhibit
a poorly defined boundary with the adjacent myometrium. The
smooth muscle cells can appear enlarged relative to the adjacent
myometrial cells. The hyperplasia of the smooth muscles can, how-
ever, be minimal, or even absent in women who have gone through
menopause [22].
Imaging
Currently, the diagnosis of adenomyosis is mostly performed by
non-invasive methods. Imaging techniques, particularly pelvic ultra-
sound and pelvic MRI, allow identification of adenomyosis lesions
within the myometrium [3].
Transvaginal pelvic ultrasound
Pelvic imaging is indispensable for diagnosing adenomyosis [3].
Suprapubic or transvaginal pelvic ultrasound constitutes a straight-
forward, minimally invasive, and inexpensive examination. Precise
criteria have been defined in the literature to establish the diagnosis
of adenomyosis. Systematic ultrasound evaluation of the uterine
morphology has been proposed (Table 1) [23]. Firstly, it involves
analysis of the uterine body: the size of the uterus, the globular
appearance, the anterior-posterior diameter, the anterior-posterior
myometrial asymmetry, the overall echogenicity, and the smooth-
ness of the uterine serous membrane. It also evaluates the junctional
zone (JZ) between the endometrium and the myometrium, which
can appear uneven, poorly defined, and interrupted or absent. Lastly,
it assesses the myometrial lesions; the affliction is considered local-
ized if it is less than 50% of the volume of the uterus or it is considered
diffuse if it is greater than 50% of the uterine volume [23]. To be
exhaustive, ultrasound evaluation needs to be systematic; certain
ultrasound criteria are more important and the association of several
of these criteria increases the probability of the diagnosis [24]. This
examination has very high degrees of specificity and sensitivity, esti-
mated to be 84% and 64%, respectively, according to a recent meta-
analysis including three studies that considered the diagnosis of
Table 1
Ultrasound features considered currently to be
typical of adenomyosis, adapted from the con-
sensus of the “Morphological Uterus Sonographic
Assessment group” (MUSA), 2015.
Ultrasound features
Asymmetrical thickening of the myometrium
Myometrial cysts
hyperechoic islands
fan-shaped shadowing
echogenic subendometrial lines and buds
translesional vascularity
irregular junctional zone
interrupted junctional zone
M. Bourdon, P. Santulli, L. Marcellin et al. Journal of Gynecology Obstetrics and Human Reproduction 50 (2021) 102228

adenomyosis when at least one sonographic criteria and two studies
when two sonographic criteria were present [25].
Pelvic magnetic resonance imaging (MRI)
MRI is an accurate and non-invasive technique usually used as an
examination of second-intention for diagnosing adenomyosis. For
certain patients, particularly those exhibiting associated pathologies
(notably in case of a myomatous uterus), recourse to MRI is necessary
[22]. Although pelvic MRI is more expensive and less available, it is a
more reproducible examination [22]. Evaluation by pelvic MRI
involves performing T1- and T2-weighted sequences. The sensitivity,
specificity, and positive and negative prediction values of MRI are
estimated to be 77.5%, 92.5%, 83.8%, and 89.2%, respectively [22].
The main direct criteria of adenomyosis are: (i) the presence of
intramyometrial foci corresponding to dilated endometrial glands.
These can be less than 3 mm in size and appear hyperintense on
weighted T2 or T1 sequences (if hemorrhagic). This sign is practically
pathognomonic, but is only found in 50% of cases [4]. (ii) There can
also be one or more posterior or anterior myometrial lesions that are
subserosal, poorly defined in T2 hyposignal by MRI, and separated
from the JZ by normal appearing myometrium. The main indirect
signs by MRI are (i) visualization of a uterus of greater size, with
smooth edges, (ii) thickening of the JZ by more than 12 mm, which is
poorly defined, affecting all of the JZ or only a part [4]. This last mea-
surement on a sagittal section appears on T2-weighted sequences as
a hypointense band at the internal side of the myometrium. (iii) The
presence of linear striations hyperintense in T2, running from the
basal layer of the endometrium toward the myometrium, (iv) An
increase in the ratio of the thickness of the JZ relative to the thickness
of the entire myometrium, measured at the same place, by more than
40% [4,26].
Classifications by MRI
Several classifications have been proposed in the literature. We
here provide details for several of them (Table 2).
An initial classification proposed by Kishi et al. defined four
adenomyosis subtypes. Subtype I represents internal, intrinsic adeno-
myosis, which contacts the JZ and the endometrium; subtype II rep-
resents adenomyosis localized to the external part of the
myometrium without reaching the internal structures; subtype III
corresponds to intramural entities confined to the myometrium; and
subtype IV (undetermined) comprises entities other than the ones
referred to previously (Table 2) [5].
Another classification has been proposed by Bazot et al., which
describes three types of adenomyosis by MRI [4]. (i) Internal
adenomyosis comprising three subtypes: focal adenomyosis, super-
ficial adenomyosis, and diffuse adenomyosis. (ii) Adenomyoma
itself comprises four subtypes: intramural solid adenomyoma,
intramural cystic adenomyoma, submucosal adenomyoma, and
subserosal adenomyoma. (iii) Posterior or anterior external adeno-
myosis, which corresponds to a subserosal myometrial mass asso-
ciated with a deep anterior or posterior endometriosis lesion
(Table 2).
Lastly, a third classification has been proposed by Chapron et al.,
which defines two main adenomyosis subtypes: diffuse internal
adenomyosis and focal adenomyosis of the external myometrium [6].
In this classification, diffuse adenomyosis is defined by the associa-
tion of two criteria: (1) a JZ of at least 12 mm and (2) a JZ/Myome-
trium ratio over > 40%. The combination of these signs by imaging
allows diagnosis of 87.5% of diffuse adenomyosis cases. Focal adeno-
myosis is characterized by the presence of a poorly defined subser-
osal mass affecting the posterior or anterior wall of the myometrium,
separated from the JZ by an area of healthy myometrium. It can be
seen in T2 hyposignal containing spots or foci hyperechogenic in T2
and sometimes hyperechogenic in T1 [4]. A single patient can also
exhibit both adenomyosis phenotypes (Table 2).
Symptomatology
The symptomatology is very heterogeneous depending on the
patients. There are no pathognomonic symptoms of adenomyosis.
Clinically, adenomyosis can result in abnormal bleeding, pelvic pain,
and infertility, although approximately 30% of patients are asymp-
tomatic (Fig. 1) [2].
Pelvic pain
Several studies have found evidence of a correlation between the
presence of adenomyosis and the presence of pelvic pain [9,11,27].
Pelvic pain, particularly dysmenorrhea, is a relatively frequent symp-
tom as it occurs in 2% to 48% of patients depending on the study
[9,11,27−30]. The intensity of the pain may correlate with the depth
of the myometrial invasion of the ectopic endometrial sites, although
it does not appear to correlate with the location of the adenomyosis
lesions within the myometrium [2,9].

Table 2
Classifications of adenomyosis lesions by MRI.

Kishi et al. 2012 Bazot et al. 2018 Chapron et al. 2017

Lesion of the internal du myometrium
Lesion of the external myometrium
Non-specific localization of the lesions
in the myometrium
Subtype 1: Intrinsic adenomyosis (of the
internal myometrium)
Subtype 2: Extrinsic adenomyosis (of the
external myometrium without reach-
ing the internal structures)
Subtype 3: Intramural affliction confined
to the myometrium
Subtype 4: Indeterminate
(does not correspond to the other
subtypes)
Internal adenomyosis (of the internal
myometrium):
- Focal adenomyosis
- Superficial adenomyosis
- Diffuse adenomyosis
External adenomyosis (subserosal myo-
metrial mass associated with a deep
endometrial lesion):
- Posterior
- Anterior
Adenomyosis:
- Intramural solid adenomyoma
- Intramural adenomyoma cyst
- Submucosal adenomyoma
- Subserosal adenomyoma
Diffuse adenomyosis of the internal myo-
metrium:
Junctional zone ≥ 12 mm and a maxi-
mal JZ/myometrium ratio > 40%.
Focal adenomyosis of the external myo-
metrium:
Poorly defined subserosal mass affect-
ing the posterior or anterior wall of the
myometrium, separated from the junc-
tional zone by an area of healthy
myometrium

3
M. Bourdon, P. Santulli, L. Marcellin et al.
Fig. 1. Symptomatology of adenomyosis.
The suggested mechanisms for the occurrence of pelvic pain are
still poorly elucidated and several hypotheses have been formulated:
(i) a perturbed immune environment leading to the secretion of algo-
genic and neurogenic substances may result in pelvic pain [31,32]
and/or (ii) pelvic pain could be a consequence of an increase in con-
tractility of the myometrium in response to hormonal and immune
changes [28,33].
Abnormal uterine bleeding
Abnormal uterine bleeding is the most common symptom
encountered in case of adenomyosis [2]. Indeed, menorrhagia is a fre-
quent cause of hysterectomy in women with adenomyosis [1]. A cer-
tain number of them also exhibit intermenstrual bleeding or pre- or
postmenstrual spotting. Some authors have concluded that the fre-
quency of abnormal uterine bleeding increases as the extent to which
the myometrium is affected by ectopic endometrial entities increases
[1,15]. Thus, abnormal uterine bleeding could depend on the thick-
ness of the JZ [34].
The pathophysiological explanation for the bleeding is not known
presently. Abnormal uterine bleeding could be the consequence of
tissue lesions secondary to cyclical bleeding of the ectopic endome-
trium. These lesions and repeated tissue repair could lead to inflam-
mation, activation of angiogenesis, and perturbation of the local
vascular system [35].
Infertility
The prevalence of infertility and spontaneous fertility in a popula-
tion afflicted with adenomyosis is still insufficiently described in
humans. In animals, a clear association has been described between
adenomyosis and primary infertility. Thus, in a study conducted in 37
baboons exhibiting adenomyosis confirmed by histology, the preva-
lence of primary infertility was significantly increased in the presence
of adenomyosis, with an OR of 20.6. This strong association persisted
even after exclusion of the cases involving associated endometriosis
[36].
In humans, several studies indicate that adenomyosis may be
associated with impairment of fertility. According to a meta-analysis
including 9 studies, the prevalence of adenomyosis in a population of
infertile women undergoing in vitro/intra-cytoplasmic sperm injec-
tion (FIV/ICSI) fertilization varied from 6.9% to 34.3% [37].
Furthermore, the mechanisms involved in the occurrence of infer-
tility in adenomyotic patients are still unclear. The infertility could be
related to: (i) immunological changes within the eutopic
4
Journal of Gynecology Obstetrics and Human Reproduction 50 (2021) 102228
endometrium [7], chronic dysperistalsis of the myometrium [33],
local hyperestrogenism, and/or lastly alteration of cell proliferation,
apoptosis, and cell adhesion at the level of the endometrium, respon-
sible for endometrial implantation anomalies [38]. The risk of infertil-
ity could also be increased by the frequent association with
endometriosis [6,19], which can also alter fertility [6,39].
Clinical profile according to the adenomyosis phenotype
The clinical profile appears to be heterogeneous according to the
patient exhibiting adenomyosis (Fig. 1). Indeed, the literature shows
that history/risk factors and the symptoms can differ depending on
the type of adenomyosis lesions in the myometrium [9]. Thus, there
are two clinical profiles according to whether the woman has focal
adenomyosis of the external myometrium or diffuse adenomyosis of
the internal myometrium (Fig. 2) [5,6,8,9,27]. There are also other
types of adenomyosis lesions within the myometrium [4,5], although
there is not sufficient data to date to identify specific clinical profiles.
In regard to the characteristics of the patients (history/risk fac-
tors), Kishi et al. have shown, with a series of 152 patients with
adenomyosis, that the patients with diffuse internal adenomyosis
were older (38.7 years vs. 36.9 years, p < 0.05) and more often had a
history of uterine curettage (32.2% vs 7.8%, p < 0.01), while those
exhibiting focalized adenomyosis of the external myometrium had
more often never been pregnant (35.3% vs. 57.6%, p < 0.05) and more
often exhibited endometriosis of the posterior cul-de-sac (92.3% vs.
25.4%). A previous study published by our team has shown that exter-
nal focal adenomyosis was observed more frequently in patients
exhibiting endometriosis, and particularly a deep form of endometri-
osis [6,40,41]. Exacoustos et al. have also shown that the patients
with a diffuse form of adenomyosis of the internal myometrium by
pelvic ultrasound were significantly older [27]. Thus, diffuse adeno-
myosis of the internal myometrium appears to occur more frequently
in older and multiparous women, and it most often involves women
who have previously undergone uterine surgery relative to focal
adenomyosis of the external myometrium. Focal adenomyosis of the
external myometrium, conversely, appears to more often affect youn-
ger women, exhibiting an associated endometriosis.
In terms of the clinical symptoms, the presence of abnormal uter-
ine bleeding and infertility appear to vary according to the phenotype
of the adenomyosis [9]. The presence of abnormal uterine bleeding,
particularly menorrhagia, is found more frequently in women exhib-
iting diffuse adenomyosis lesions of the internal myometrium [9].
Indeed, in a recent study, a marked increase in menorrhagia was
noted in the women afflicted with internal adenomyosis relative to
M. Bourdon, P. Santulli, L. Marcellin et al.
Fig. 2. Two phenotypes of adenomyosis: Diffuse internal adenomyosis and focal adenomyosis of the external myometrium.A- Diffuse internal adenomyosis, with diffuse enlarge-
ment of the uterus and thickening of the junctional zone; 1- Transvaginal pelvic ultrasound (TVUS), Sagittal view; 2- Diffuse internal adenomyosis, Pelvic magnetic resonance imag-
ing (MRI), T2 weighted image, Sagittal view. B- Focal external adenomyosis (white arrows) next to deep infiltrating endometriosis of the torus uterinum with bowel involvement
(white stars); 1-TVUS, Sagittal View; 2- MRI, T2 weighted image, Sagittal view
those exhibiting focal adenomyosis of the external myometrium [9].
This difference persisted after exclusion of the patients afflicted with
associated leiomyomas. Other studies have also suggested a differ-
ence according to the phenotype of the adenomyosis. Pinzauti et al.
noted an increase in menorrhagia in a population of 53 women with
diffuse adenomyosis relative to a population not afflicted with adeno-
myosis [11]. An association between the diffuse form of the internal
myometrium and menorrhagia has also been described in a recent
study comparing women with adenomyosis diagnosed by ultrasound
[27]. Similarly, not all adenomyosis phenotypes are associated with
infertility. In a study of 500 women, it was shown that the presence
of focal adenomyosis of the external myometrium was significantly
associated with the presence of primary infertility (p < 0.01), while
diffuse adenomyosis of the internal myometrium was not associated
with primary or secondary infertility [8]. Furthermore, based on a
multinomial regression model adjusted on the age of the women, the
association with endometriosis and/or with fibromas, the presence of
focal adenomyosis of the external myometrium was identified as an
independent factor associated with infertility (OR 1.9; CI 95%: 1.1
−3.3) [8]. Thus, primary infertility appears to be more frequent in
women with adenomyosis lesions of the external myometrium.
Adenomyosis lesions of the external myometrium and those of
the internal myometrium are responsible for quite distinct clinical
presentations, which suggests two different adenomyosis entities.
Conclusion
Adenomyosis can be diagnosed by anatomopathological examina-
tion of the uterine myometrium but also, in recent years, by imaging
(transvaginal pelvic ultrasound and/or MRI). These imaging tools
have allowed different types of adenomyosis lesions to be identified,
5
Journal of Gynecology Obstetrics and Human Reproduction 50 (2021) 102228
based on their presentation and their localization in the myome-
trium. At the clinical level, adenomyosis is a heterogeneous disease
and the profile of patients with adenomyosis as well as the symptom-
atology appear to be linked to the adenomyosis phenotype, particu-
larly with the diffuse nature of lesions in the internal myometrium or
focal lesions within the external myometrium. In order to provide
the most suitable treatment for patients with adenomyosis, a precise
evaluation of the symptomatology but also of the phenotype of the
adenomyosis by imaging appears to be necessary. At present, the
therapeutic options are multiple although none of them are specific
for adenomyosis and no medicinal therapeutic allows being ‘cured’ of
adenomyosis. Additional research appears to be necessary in order to
develop future curative therapeutics that are tailored to the adeno-
myosis phenotype.
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