Caring for individuals with a difference of sex development (DSD): a Consensus Statement

Abstract

The term differences of sex development (DSDs; also known as disorders of sex development) refers to a heterogeneous group of congenital conditions affecting human sex determination and differentiation. Several reports highlighting suboptimal physical and psychosexual outcomes in individuals who have a DSD led to a radical revision of nomenclature and management a decade ago. Whereas the resulting recommendations for holistic, multidisciplinary care seem to have been implemented rapidly in specialized paediatric services around the world, adolescents often experience difficulties in finding access to expert adult care and gradually or abruptly cease medical follow-up. Many adults with a DSD have health-related questions that remain unanswered owing to a lack of evidence pertaining to the natural evolution of the various conditions in later life stages. This Consensus Statement, developed by a European multidisciplinary group of experts, including patient representatives, summarizes evidence-based and experience-based recommendations for lifelong care and data collection in individuals with a DSD across ages and highlights clinical research priorities. By doing so, we hope to contribute to improving understanding and management of these conditions by involved medical professionals. In addition, we hope to give impetus to multicentre studies that will shed light on outcomes and comorbidities of DSD conditions across the lifespan.

Full text

Differences of sex development (DSDs; also known as
disorders of sex development) comprise a large group of
congenital conditions of the urogenital tract and repro-
ductive system, affecting human sex determination and/or
differentiation. Nomenclature remains controversial;
current medical classification is largely based on the
genetic status of the patient1 (FIG.1). Our knowledge
of DSDs has greatly evolved in the past decade owing
to cutting- edge research on mammalian sex develop-
ment and the genetic mechanisms underlying DSDs2–4.
In parallel to this research, several clinical outcome stud-
ies have been conducted; however, the results of these
studies are inconclusive owing to small and heteroge-
neous samples, variable methodology and the inclusion
of older, sometimes outdated, treatments and surgical
techniques. The lack of conclusive outcome data for
patients with DSDs has triggered large- scale collabo-
rative research that initially focused on basic science
projects (such as the EuroDSD project) and since 2012
began addressing clinically oriented issues and outcomes
(for example, dsd- LIFE). These clinically oriented
studies have provided new insight on historical trends5,
comorbidities6 and outcomes of specific conditions7.
The development of international registries, such as the
I- DSD Registry, the I- CAH Registry and the DSD
Translational Research Network8,9, was crucial in the
development of collaborative research projects. Now that
the registries are established, however, emerging chal-
lenges include establishing ways for patients to access
their personal data and developing methods for the
optimal securement of privacy.
Recommendations from 2014, 2015 and 2016 address
diagnostic strategies and provide guidance for a holistic
clinical approach, mostly during childhood and ado-
lescence1,10,11. Holistic approaches to treatment require
multidisciplinary care by teams of relevant subspecialists
working in close collaboration and a strong peer support
network. Primary subspecialties include endocrinology,
EXPERT CONSENSUS DOCUMENT
Caring for individuals with a
difference of sex development (DSD):
a Consensus Statement
MartineCools
1*, AnnaNordenström2, RalitsaRobeva3, JoanneHall4,
PuckWesterveld5, ChristaFlück6, BirgitKöhler7, MartaBerra8, AlexanderSpringer
9,
KatinkaSchweizer10 and VickiePasterski11, on behalf of the COST Action BM1303
working group 1
Abstract | The term differences of sex development (DSDs; also known as disorders of sex
development) refers to a heterogeneous group of congenital conditions affecting human sex
determination and differentiation. Several reports highlighting suboptimal physical and
psychosexual outcomes in individuals who have a DSD led to a radical revision of nomenclature
and management a decade ago. Whereas the resulting recommendations for holistic,
multidisciplinary care seem to have been implemented rapidly in specialized paediatric services
around the world, adolescents often experience difficulties in finding access to expert adult care
and gradually or abruptly cease medical follow- up. Many adults with a DSD have health- related
questions that remain unanswered owing to a lack of evidence pertaining to the natural evolution
of the various conditions in later life stages. This Consensus Statement, developed by a European
multidisciplinary group of experts, including patient representatives, summarizes evidence- based
and experience- based recommendations for lifelong care and data collection in individuals with
a DSD across ages and highlights clinical research priorities. By doing so, we hope to contribute to
improving understanding and management of these conditions by involved medical professionals.
In addition, we hope to give impetus to multicentre studies that will shed light on outcomes and
comorbidities of DSD conditions across the lifespan.
*e- mail: martine.cools@
ugent.be
https://doi.org/10.1038/
s41574-018-0010-8
ConSEnSUS
Statement
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urology, gynaecology, andrology, psychology, nursing,
social work, genetics and medical ethics. Input from
support and service user groups has been paramount
in defining new research questions. As a result, clini-
cal studies focusing on comorbidities, treatment effects,
outcomes in adults and psychosocial issues are placed
high on the research agenda. How patients experience
having a DSD and how they cope with medical proce-
dures need to receive more attention in research and
clinical practice12.
Indeed, insufficient, or inadequate, medical care
might result in adverse patient outcomes that, in
turn, could impede participation in studies aimed at
further improving clinical care. For example, health-
care systems that are unable to provide longitudinal
holistic care, with coordinated transition to adult
services, or that proceed with treatments with poor
knowledge of the condition (for example, owing to
lack of subspecialties) can cause mistrust and/or a lack
of engagement with health- care professionals among
adults with a DSD. Other factors that might result in
adverse patient outcomes include non- acceptance of
the chronic condition or avoidance of medical care due
to negative experiences of medical procedures during
childhood13,14. The rarity and complexity of the vari-
ous conditions in combination with decentralization
or lost follow- up of patients make studies including
meaningful numbers of adults living with a DSD
challenging. The resulting dearth of evidence- based
guidelines for this cohort is then compounded further
by demotivation of patients and caregivers to invest in
sustainable health measures.
To address the aforementioned difficulties, we need
to ensure that clinicians who do not have regular expo-
sure to patients with a DSD have detailed guidance in
clinical review and data collection for patients at various
life stages. Ensuring this would increase the potential for
meaningful results from clinical research and decrease
the potential for bias in clinical assessments, thus facil-
itating longitudinal, multicentre studies as the founda-
tion for evidence- based management and exchange of
consistently formatted data in research networks such
as I- DSD15. Finally, adherence to evidence- based proto-
cols can serve as a quality indicator for defining centres
of expertise. Many features and management issues are
shared by the different DSDs. Most of the areas that are
extensively discussed here mainly pertain to the 46,XY
DSD, 46,XX DSD and 45,X/46,XY DSD groups (FIG.1).
Turner syndrome and Klinefelter syndrome, which
are grouped under the wider DSD umbrella, require a
similar multidisciplinary approach. For these condi-
tions, however, clinical guidelines already exist and are
widely used; therefore, they will not be addressed in this
Consensus Statement16–18.
Standardizing the longitudinal assessment of indi-
viduals with a DSD across centres might also provide
evidence for or against controversial procedures — such
as surgical management of genitalia with an atypical
appearance19–21 — and clinicians could then make deci-
sions on the basis of careful consideration of relevant
parameters. Parameters clinicians need to consider
when deciding on the appropriate treatment strategy
include body appearance, psychosocial support, soci-
ocultural influences, gender- related development and
genetic and/or biochemical background in addition to
ethical, legal and human rights implications1. Intersex
activists have encouraged legislative bodies worldwide
to ban elective, irreversible genital surgery without the
individual’s informed consent, and in some countries,
such as Germany, legislative recommendations in this
direction have been instituted22. In the absence of long-
term outcome data that support or disfavour deferring
genital surgery, there is currently little evidence that
surgical practice has dramatically changed in recent
years20,23. However, there is a broad consensus that
alternatives to surgery, such as supporting families in
parenting children who have a genital difference and/or
facilitating psychological adjustment, have not been
fully developed or supported by governmental health-
care systems. Furthermore, there is a belief that stake-
holders, most notably patient groups, have not been
sufficiently consulted in this matter24,25. Finding ways to
raise resilient children with atypical- appearing genitalia,
defining the precise role of (early) genital surgery in the
management of DSDs and collecting data on psycho-
social adjustment and outcomes in both children who
have undergone surgery and those who have not are
considered top priorities.
From a patient perspective, structured and continued
follow- up might increase beneficial interactions with
health- care professionals, potentially enhancing under-
standing of the specific conditions, knowledge of future
medical needs and compliance with the treatment26. A
predefined schedule would greatly support patients and
health- care staff during the vulnerable transition phase
from adolescence to adulthood, encourage patients to
prepare for discussions with caregivers and facilitate
movement from one clinic to another by providing a
personal summary of medical history27–29.
In this Consensus Statement, we aim to address the
above outlined weaknesses in patient- centred care and
research by reviewing existing evidence and, where this
is absent, providing recommendations for holistic care
and data collection in individuals with a DSD across
Author addresses
1Department of Paediatric Endocrinology, Ghent University Hospital, University of Ghent,
Ghent, Belgium.
2Department of Women’s and Children’s Health, Paediatric Endocrinology Unit,
Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
3Clinical Center of Endocrinology and Gerontology, Medical University- Sofia, Medical
Faculty, Sofia, Bulgaria.
4CAH support group, Chester, UK.
5DSDNederland, Amsterdam, Netherlands.
6Paediatric Endocrinology and Diabetology, Department of Paediatrics and Department
of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern,
Switzerland.
7Department of Paediatric Endocrinology, Charité University Medicine, Humboldt
University Berlin, Berlin, Germany.
8Department of Obstetrics and Gynaecology, Ramazzini Hospital, AUSL Modena,
Modena, Italy.
9Department of Paediatric Surgery, Medical University Vienna, Vienna, Austria.
10Institute for Sex Research and Forensic Psychiatry, University Clinic Hamburg-
Eppendorf, Hamburg, Germany.
11Department of Psychology, University of Cambridge, Cambridge, UK.
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ConSenSuS Statement

ages. Definitions of several key terms used in this article
are provided in BOX1.
Methods
This Consensus Statement was created within the
framework of the European Cooperation in Science
and Technology (COST) Action ‘DSDnet’, representing
23 European Union member states, 3 near- neighbouring
countries and 5 international partner countries. The rec-
ommendations were developed following work around
the theme ‘standardization of clinical assessment of indi-
viduals who have a DSD’ by a focus group of clinicians
from relevant disciplines and patient representatives.
Data were identified by searches of the PubMed and
Embase databases and reference lists from relevant
papers; only original research papers and reviews later
than 2000 and published in English were considered. All
data were subject to extensive group discussions, taking
place at face- to-face meetings, until consensus on actual
status summary and recommended actions was reached.
The resulting document was posted on a members-
only area of the DSDnet website in August 2017 for a
vetting process by all stakeholders, including clinicians,
scientists, ethicists, advocates and patient and parent
representatives. General approval of the final Consensus
Document was reached in September 2017.
46,XY DSD
Disorders of gonadal
development
• Complete or partial
gonadal dysgenesis,
monogenic forms
(for example, SRY,
NR5A1 and WT1)
• Testes regression
• Ovotesticular DSD
• Syndromic forms
Disorders of androgen synthesis
• Associated solely with androgen
biosynthesis defects (mutations or
deficiencies in HSD17B3 and
SRD5A2, for example)
• Associated with congenital adrenal
hyperplasia and early androgen
biosynthesis defects (mutations
and/or deficiencies in STAR,
CYP11A1, HSD3B2, POR
and CYP17A1)
• Associated with placental
insufficiency or endocrine
disruption
• Syndromic forms (for example,
Smith–Lemli–Opitz)
Disorders of androgen
action
Complete and partial
androgen insensitivity
Persistent Müllerian
duct syndrome
Due to mutations or
deficiencies in AMH
and AMHR2
Unclassified disorders
• Hypospadias of unknown
origin
• Epispadias
• Complex syndromic
disorders
46,XX DSD
Disorders of gonadal
development
• (Ovo)testicular DSD
• Monogenic forms of
primary ovarian
insufficiency (mutations
in genes involved in
gonadal (ovarian)
development; for
example NR5A1
and WT1)
• Syndromic forms
Disorders of androgen excess
• Aromatase (CYP19A1) deficiency
• Congenital adrenal hyperplasia
(mutations and/or deficiencies in
CYP21A2, HSD3B2, CYP11B1
and POR
• Luteoma
• Iatrogenic
Unclassified disorders
• MRKH type I and II syndrome
• Complex syndromic disorders
45,X
Turner syndrome and variants
Sex chromosomal DSD
47,XXY
Klinefelter syndrome and variants
45,X/46,XY and 46,XX/46,XY
• Mixed gonadal dysgenesis
• Chimerism
Primary cause Secondary root Tertiary root
Fig. 1 | Classification of DSDs. Disorders of sex development (DSDs) are classified into three main groups on the basis of the karyotype of the affected
individual (primary cause). Each main group encompasses several subgroups (secondary root) that orient towards a specific diagnosis (tertiary root).
MRKH, Mayer–Rokitansky–Küster–Hauser syndrome.
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ConSenSuS Statement

Individualized care plan
Informed consent
Before undertaking any diagnostic and/or therapeu-
tic procedure, patients, or parents and/or guardians of
minors, need to be thoroughly informed by the clinical
team and give consent. For sensitive and/or irreversible
procedures, such as genital surgery, we advise that the
intervention be postponed until the individual is old
enough to be actively involved in the decision whenever
possible. Informed patient and/or parental consent is also
a prerequisite to collect data and biomaterials for research
purposes; examples of such informed consent documents
in multiple languages can be found in the I-DSD Registry.
A discrepancy is often perceived between research top-
ics proposed by scientists and what individuals who have
a DSD consider important. In addition, many patients
have felt abused in past research projects or mistreated
by health professionals12,30. In response to these problems,
collaborative networks, such as the DSDnet and ‘dsd-
LIFE’ consortia, have been formed between research-
ers, health professionals, patient families and support
groups. The dsd- LIFE study identified the research needs
that patients and parents consider apriority (BOX2). In
addition, in the newly established European Reference
Network (ERN) covering rare endocrine conditions
(Endo- ERN), patient participation in research and data-
base management is considered crucial. Collaborations
between patients, parents, health- care professionals and
researchers are based on trust and confidentiality
and must be handled with utmost care.
Diagnostic investigations
All individuals with a suspected DSD need a thorough
diagnostic evaluation, including an extensive whole-
body and genital physical exam, biochemical and
genetic investigations and imaging studies, with results
discussed in the multidisciplinary team10. The ultimate
goal is to obtain a diagnosis at the molecular genetics
level to allow prognostic predictions and genetic coun-
selling and to set up an individualized management
plan. Although the advent of genome- wide sequencing
technologies has improved diagnostics, this goal cannot
be achieved in ~50% of individuals with a 46,XY DSD,
which highlights the importance of hitherto uniden-
tified regulatory mechanisms11,31,32. Opportunities for
advanced genetic work- up are currently mostly availa-
ble through collaborative research projects that recruit
patients enrolled in registries and networks; hence,
participation of health- care providers in such networks
is of direct benefit for patients. Biochemical work- up is
equally important as it can, even in the absence of a
genetic diagnosis, inform underlying pathology and
hormonal treatments. Currently, chromatographic,
mass spectrometric methods are recommended for
exact steroid hormone measurements. However, these
methods are not yet widely available, and standardiza-
tion between laboratories has only just started33. As the
diagnostic quest can be long and hard to bear for affected
families, such uncertainty should not result in hesitation
towards outlining the management plan and addressing
pending clinical issues (for example, those regarding sex
assignment and information sharing).
Information and psychological support
Patients and parents are often facing a complex and
previously unknown set of circumstances when they
first learn about a DSD diagnosis. In addition, as part of
holistic care, after the provision of medical information
and clinical guidance patients and families should stay
in regular contact with the clinical team (for example,
once every 1–2 years) even in the absence of medical
problems or treatments. Initial emotions can be over-
whelming, and continued psychosocial support is often
needed when families are processing the diagnosis as
well as for further decision- making34. Such counselling
might also provide support for communication within
a patient’s social network and for the development of a
personalized diagnosis- specific vocabulary, in addition
Box 1 | Glossary of common terms
Chromatographic, mass spectrometric methods
Tandem laboratory investigative techniques that can be used to analyse biochemical,
organic and inorganic compounds commonly found in complex samples of
environmental and biological origin.
DSDs
Congenital conditions in which chromosomal, gonadal or anatomical sex has been
compromised, usually owing to a genetic mutation. Use of the term ‘disorder’ is
controversial in the context of naturally occurring variations.
Gender
The psychological experience of being male, female, both or neither (typically used
regarding social and/or cultural differences rather than biological ones).
Gender identity
The core sense of the gendered self as male, female or other.
Gender role
Behaviours, preferences and traits that differ, on average, between males and females
in a given culture and historical period.
Genome- wide sequencing
A process used to determine the sequence of most of the DNA content (whole- genome
sequencing) or most of the protein- encoding exons found in the genome (whole- exome
sequencing) of an individual.
Genotype
The genetic make- up of an individual organism.
Holistic health care
A system of comprehensive patient care that considers the physical, emotional, social,
economic and spiritual needs of the patient. Holistic care in DSDs also considers the
needs of family members of patients.
Intersex
The term that was used prior to the 2006 Consensus Statement and that has been
replaced by DSDs, mainly in the medical literature. Some individuals have
re-appropriated the term and identify themselves as ‘intersex’, whether or not a DSD
has been diagnosed.
Phenotype
The set of observable characteristics of an individual resulting from the interaction of its
genotype with the environment.
Sex
The state of being male or female (typically used regarding biological differences that
include sex chromosomes, gonads and internal and/or external reproductive
structures).
Sexual orientation
The direction of sexual attractions to males, females, both or neither.
DSDs, differences of sex development (also known as disorders of sex development).
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ConSenSuS Statement

to providing help for dealing with their feelings.
Patient- centred support focuses on individual deter-
minants of coping, such as personal attitudes, life
experiences, cultural and religious background and
eventual socio- economic barriers; however, it should
also address fears, concerns and questions that are rel-
evant for individuals and families across all DSDs (for
example, how parents and/or guardians can inform
their child about their DSD and how they can deal
with negative reactions). If the families and patients
have written information on these issues available at all
times, it might further help them gain self- confidence
to deal with the situation.
Tension exists with regards to the use of the terms
‘DSD’ versus ‘intersex’. Explaining the condition as a
natural variation and promoting a non- binary view
on sex and gender in general might alleviate this friction
and direct the focus of discussion towards the provision
of optimal care. If identified, most individuals prefer to
use the specific name for their condition rather than the
broader DSD or intersex terms25.
Transparent and complete information is crucial for
helping patients cope throughout their lives, and patients
often fully understand the information only after sev-
eral appointments with health- care professionals12,26.
Diagnostic and treatment- related information should be
given in the context of typical sex differentiation and/or
development for improved conceptual grasp of naturally
occurring variations. The benefits and risks of eventual
interventions should be discussed with the patient and
their families as part of a joint process. Today, health-
care providers generally agree that all children who
have a chronic condition should be informed early. This
agreement holds true for DSDs35 and is a continuous
process at the child’s own pace. Explaining the condition
in an age- appropriate language to the child and adoles-
cent facilitates acceptance and can help to reduce fear
and stigma. Clear and consistent communication pro-
motes confidence in the medical team and enables future
joint decision- making and therapeutic compliance36
(BOX3; FIG.2). In cases where parents and/or guardians
are reluctant to share developmentally appropriate and
important clinical details with their children, a brief
period of delay in providing this information is some-
times inevitable. At the same time, the multidisciplinary
team has an important task in sensitively guiding the
parents towards enhanced acceptance of the condition
and reducing fears they might have around the process
of informing their child.
Fertility issues are often sensitive to communicate.
Nevertheless, informing individuals before adoles-
cence in a timely and progressive manner is considered
appropriate37. Although the possibility of transmitting a
genetically determined condition can be a major con-
cern, and germ cells are absent or severely reduced in
number in the gonadal tissue of most individuals with
a DSD condition, some options, such as early tissue
cryopreservation, are available for a limited number of
patients38. Although not yet clinically available, invitro
maturation of immature sperm or oocytes and har-
vesting germ cells from induced pluripotent stem cells
are promising future techniques39. Therefore, stepwise
decision- making in relation to gonadal surgery can
guide families through this difficult process. Possibilities
for fertility preservation using experimental procedures,
with their ethical and economical drawbacks, should
be carefully balanced against germ cell cancer risk or
unwanted hormone production and considered along-
side the promotion of other ways of having a family, such
as adoption40.
Transition of care
Much of the literature pertaining to the medical care of
individuals with a DSD comes from paediatric practice
and the adult perspective is not commonly represented.
Children often transition from specialized paediat-
ric care to general adult or primary care services with
potential loss of confidence in provision of DSD- specific
medical management. From there, it is sometimes dif-
ficult to find a way back to an informed clinical service,
especially because adult specialists who have a detailed
and in- depth training in DSDs are rare. As a result,
many adult patients describe difficulties finding good
endocrine care41.
Ideally, the adult specialist that a patient is being trans-
ferred to would be involved early in the transition process.
To build a trustful relationship, an open discussion of all
available relevant medical data, including progressive
information on any hitherto insufficiently communi-
cated aspects of the condition, is crucial. Evolving gender
identity and sexual orientation might also become impor-
tant themes in the transition to adulthood. Experts in the
field have developed a DSD- specific transition checklist
for service users and multidisciplinary teams27,42 (FIG.2).
Multidisciplinary care in adulthood
Multidisciplinary care is equally important in adult-
hood as it is in childhood and can involve specialists
from an even wider range of disciplines. Individuals
with congenital adrenal hyperplasia (CAH) require life-
long glucocorticoid treatment and usually additional
mineralocorticoid replacement43. Sex hormone replace-
ment therapy (HRT) can be given to adults with non-
functional or partially functioning gonads to promote
cardiovascular and bone health as well as general well-
being. In the absence of DSD- specific guidelines, clini-
cal practice usually follows published recommendations
that have been developed for individuals with Turner or
Klinefelter syndrome18,44.
Fertility is markedly reduced in almost all forms of
DSDs. In CAH, optimal hormonal control is required
in women who seek pregnancy and in men who have
testicular adrenal rest tumours45. Assisted reproduc-
tive techniques can offer fertility prospects to some
Box 2 | Research priorities for patients and parents
•Information management
•Parental support
•Treatment choices and effects on health
•Comorbidities and care through the lifespan
•Tumour risk
•Outcomes in children and adults
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ConSenSuS Statement

individuals with a DSD. Microdissection testicular
sperm extraction (micro- TESE) could be an option
for some men who have no sperm in their ejaculate,
provided that sperm is present in the testis biopsy46. In
2015, the first live births after uterus transplantation
in women with Mayer–Rokitansky–Küster–Hauser
(MRKH) syndrome were reported47. In women with a
46,XY DSD who have a uterus, successful pregnancies
after egg donation have been described, but numbers
are too low to allow conclusions regarding indications
and success rates48,49. Careful and sensitive counsel-
ling about fertility chances as well as discussing val-
uable alternatives, such as adoption, are paramount.
Management of vaginal hypoplasia is complex and
multifaceted. Apart from a central role for the team
psychologist, treating vaginal hypoplasia requires
expertise with several treatment options50.
As a result of uncertainty regarding the genital aspect
and/or function, and possibly impaired body image,
many individuals who have a DSD fear intimacy and
report anxiety and distress related to sexuality, resulting
in a tendency to delay or avoid sexual experience51. The
gynaecologist and urologist, along with the team’s sex-
ologist or psychologist, are well placed to discuss such
issues. Psychological support and counselling can also be
offered to adults with a DSD at one or more occasions in
life. Topics include dealing with the disclosure of diag-
nostic results or the condition itself, attaining medical
files and, in patients who have not been previously or
fully informed of the DSD, learning one’s story. In psy-
chotherapy, the loss of body integrity, sexual fear and
anger towards parents and the medical system are fre-
quent concerns52. Importantly, engaging with (online)
support groups, individual peer support and forging
partnerships between communities, professionals and
voluntary groups have proved beneficial for adolescents
and adults living with DSDs and should be encouraged
whenever possible53.
Hurdles in practical implementation
With respect to the recommended provision of care by
specialized multidisciplinary teams, logistical practi-
calities have meant that many individuals with a DSD
continue to be followed by single specialists ((paediatric)
endocrinologists, urologists or gynaecologists).
Implementation of multidisciplinary- team-related
guidelines requires drastic centralization and structural
collaboration of reference centres in large networks,
such as the recently established ERNs. The aims of such
guidelines should prioritize the development of, and
adherence to, standard care protocols and data collection
while investing in sustainable registries that promote
secure exchange and analysis of clinical data according
to FAIR (findable, accessible, interoperable and reusable)
principles54. Shared diagnostic strategies, research exper-
tise and biobanks within the network can overcome
differences in health- care levels. Patient engagement, at
the level of both individual health- care providers and
networks, is paramount. In some centres, peer counsel-
ling is a fundamental component of care before critical
decision- making (for example, related to genital sur-
gery). Others have, in collaboration with parents and
representatives, developed web- based decision- support
tools55. There are examples of support groups investing
in the professional training of family members willing
to provide peer support30. Indeed, from our experience,
this training is indispensable as it enables the peer to
provide non- judgemental support to the patients and it
informs families in a way that encourages them to make
their individual decisions.
Within the Endo- ERN, patients are represented at all
levels. Patients are actively involved in network govern-
ance and development and/or the critical appraisal of
network- related protocols and identified research pri-
orities. Although such developments have been strongly
encouraged by the European Commission’s Action Plan
for Rare Diseases, they await further legislative and
financial support from governmental bodies along with
a definitive switch to a patient- centred care paradigm.
Further development of peer support will require major
investments in training programmes and remuneration
of provided time and expertise.
Suggested data collection across ages
Assessment of genital status and follow- up
Impaired body experiences, such as decreased body sat-
isfaction or decreased feeling of attractiveness in adults
with a DSD, have resulted, in part, from past negative
experiences12. Therefore, all genital assessments should
be limited to a minimum and performed with great
caution and with explicit consent from patients and
Box 3 | Essential components of psychosocial care to affected families
Basic requirements for dealing with patients
•Acknowledge variety, complexity and individuality
•Create an atmosphere of appreciation and acceptance
•Provide time, empowerment and encouragement
Information for parents
•Biological: explain the condition as a naturally occurring variation
•Medical: explain sex and gender as non- binary concepts and in the context of sex
determination and differentiation; provide precise information on the specific condition;
provide information on vital, functional and elective medical interventions, including risks
and benefits; and offer alternatives (for example, guidance on how to tackle potentially
difficult situations and on how to raise resilient children who have a genital difference)
•Gender- related: discriminate between childhood (play) behaviour and adult gender
identity; explain that the initial decisions on social gender role may be subject to later
change according to the self- expression of the developing child; and put forward
gender contentedness as the ultimate goal
•Use sensitive and respectful language (for example, avoid using terms such as
malformation and disorder)
•Communication: listen, repeat information and ask for questions
•Promote contact with support groups and participation of appropriately trained
peers in the decision- making process or in the multidisciplinary team
Psychological counselling
•Discuss communication within the family and social environment and support
decision- making on (provisional) gender role, medical interventions and judicial
options or regulations (for example, birth certificate entry)
•Promote acceptance of individual development
•Avoid emotionally driven decisions, delay non- urgent decisions (such as those on
surgery) until psychological counselling has been given and promote participation
of trained peers in the decision- making process
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ConSenSuS Statement

parents and or/guardians. Repeated genital exams, med-
ical photography without appropriate informed consent
and the presence of multiple health professionals dur-
ing physical examination should be strictly avoided.
Recommendations on how to perform necessary gen-
ital exams in children who have genital differences, and
for preparing the child for this procedure, have been
described elsewhere56.
Genital assessment in neonates, children and adolescents.
In male neonates and infants, description of exter-
nal genitalia is facilitated by the use of a specifically
designed, quantitative scoring system, the external mas-
culinization score (EMS)57. A modified, non- binary ver-
sion, applicable in both boys and girls and which aims to
be more objective than the widely used Prader score58,
is currently being validated in a European multicentre
study. The anogenital distance correlates with prenatal
androgen exposure, but standardization of this meas-
urement is yet to be established59. Prepubertal girls, in
general, do not require assessment of the vaginal status,
especially in the absence of previous surgery. The indica-
tion and timing of such a procedure should be individu-
alized but are usually not indicated before (induction of)
puberty. When a uterus is present, a gynaecological
examination should determine whether anatomy allows
trouble- free menstrual flow41. When the measurement
of vaginal length and/or vaginal examination in a puber-
tal girl without a uterus is planned (a procedure that is
conducted mainly for deciding whether to use vaginal
dilation therapy and then supporting the therapy), the
need for local or general anaesthesia should be discussed
and agreed upon with the individual. Reference values
for genital dimensions in adult women, but not teenage
girls, have been published elsewhere60.
Long- ter m outcome of surgical procedures. Reconstructive
surgery has always been a substantial part of DSD care
and has remained so for many years seemingly without
debate. However, this has changed dramatically following
disquieting reports of unfavourable outcomes, including
high complication and/or reoperation rates and patient
dissatisfaction61–65. A more patient- centred approach has
been adopted and was informed by public discussions66,67.
Modern reconstructive surgery claims that it is possible
to create functionally and cosmetically normal- appearing
genitalia; however, there is still no consensus regarding
indication, timing or procedures of choice20,68.
The lack of consensus is partially driven by a dearth of
relevant, systematic data, which is due to the rarity
of the conditions, the heterogeneity of presentations,
the loss of patients from follow- up into adulthood and the
long interval between surgery and time of data collection.
As a consequence, many studies report on long- term
results of surgical techniques that are no longer in use50,69.
As legal liability of genital surgery becomes increasingly
important, centralization of expertise and structured
assessment, audit and meticulous documentation of out-
comes in prospective registries are paramount19,21. Such
assessments must include documentation of complica-
tion rate, functional outcome (micturition (urination)
and sexuality), cosmetic outcome, quality of life, psy-
chosexual functioning and, finally, re- evaluation of the
indication. Although genital surgery can involve a radical
approach to the urinary tract, the effects on urinary func-
tion and the pelvic floor (including safe urine storage
and drainage, urinary continence and risk of infection)
are often insufficiently addressed70. Validated tools are
available for clinical assessment and self-assessment
of masculinizing surgery outcomes, including
HOPE, HOSE, PPS and SAGAS- M71–74. Reliable tools
Age 4 years Age 6 years Early puberty Late pubertal age Adulthood
Information to child
about sex, gender and
differences has started
• Continue information
and answer questions
• Discuss puberty
• Consider introducing
privacy during PE
• Privacy during PE
• All information given
• Check knowledge
• Discuss transition
• Organize transition
• Joint consultation(s)
• Check knowledge
and autonomy
• Continued updates of
all information
• Discussion of recommended
follow-up visits and screenings
Psychosocial and peer support
• Words and vocabulary
• Principles of body
functioning, hormones
and condition
• Naturally occurring
variations
• Play behaviour
• Shame, secrecy and
guilt
• Condition-typical aspects
of body functioning
• Naming condition
• Puberty (induction)
• Fertility
• Gendered-type behaviour
• Bullying and isolation
• Chromosomes
• Sexuality
• Vaginal hypoplasia
• Testes prostheses
• GCC surveillance
• Gender contentedness
• Peers and relations
• Fertility and gamete
preservation
• Delayed gonadectomy
and/or clitoral surgery
• Gender contentedness
• Partnership and sexual
functioning
• Overall QoL
• Quality of sexual life
• PS functioning
• Fertility issues
• Gender contentedness
Timing and topics might vary largely between individuals
Information provided to affected individual
Information provided to parents
Fig. 2 | Multidisciplinary care and data collection in DSDs across ages.
Multidisciplinary care and data collection begins at diagnosis and continues
across the lifespan of the individual. The focus of the information process
gradually shifts from parents to the affected child. Psychological and peer
support are key elements at all ages. Although timing and topics may vary
according to individual circumstances, it is generally agreed that children
should be informed about their condition at an early age. Suggested themes
to be discussed by team members are shown in blue boxes at the top of the
figure, and (non- exhaustive) lists of important topics within these themes
are represented in pink boxes in the centre of the figure. DSDs, differences
of sex development; GCC, germ cell cancer ; PE, physical examination; PS,
psychosexual; QoL , quality of life.
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ConSenSuS Statement

for assessing outcomes of feminizing surgery are
needed as today clinicians must heavily rely on their
personal experience75.
Germ cell cancers. The various forms of XY and X/
XY DSD have a variable risk of developing a gonadal
germ cell cancer, which is further modulated by
patient age, location of the gonad and, possibly,
genetic predisposition76 (FIG.3a). The risk is much
higher in men and women with gonadal dysgenesis,
especially forms that arise from early gonadal differ-
entiation defects, such as mutations in SRY and WT1,
than in individuals with ovotesticular DSD or with
hormone synthesis or action disorders (for example,
androgen insensitivity syndrome)77–81 (FIG.3b). The
underlying pathogenic mechanisms and proposed
management were reviewed elsewhere in 2015 and
2017 (REFS76,82). An increasing number of adults with
a DSD have retained gonads1. Only in the coming
decades, and with meticulous documentation of all
factors involved, will the effects of advancing age,
concomitant diseases, inadequate HRT, use of other
medications or long- term exposure to environmental
disruptors and lifestyle habits on the development
and prognosis of gonadal cancer become evident.
While awaiting these new data, and in the absence
of reliable tumour markers or imaging technologies
for early detection of precursor lesions, it seems
prudent to consider gonadal biopsies to exclude the
presence of germ cell neoplasia insitu or gonadoblas-
toma in most individuals with 46,XY or 45,X/46,XY
DSD with retained gonads. Given that the age of
distribution for testicular germ cell cancers is well
established, such biopsies are best performed in late
adolescence82,83.
Somatic assessment
The developmental origin of DSD conditions and the
effect they can have on the functioning of several organ
systems warrant extensive somatic assessment of all
individuals presenting with a DSD, irrespective of age
(FIG.4). A detailed physical examination should be aimed
at excluding anomalies of other organ systems, such as
heart, lungs, kidneys or the skeleton, and of syndromic
features, such as short fourth metacarpal or metatarsal in
individuals who have 45,X/46,XY DSD or large uplifted
earlobes as seen in children who have Mowat- Wilson
syndrome6,84.
The standardization of somatic assessments is cru-
cial to secure the validity of cross- centre data pooling
with the aim of revealing hitherto unrecognized
health consequences and outcomes. Indeed, scarce
data suggest that adults who have a DSD experience
more health problems than the general population85,86.
Not surprisingly, morbidities related to deficiencies in
or treatment with sex steroids or glucocorticoids are
over- represented. Although most immediate effects
of HRT, and their importance for general well- being
and quality of life in adulthood, are well known, the
beneficial effects of HRT on specific brain functions,
such as cognition or emotional processing, especially in
elderly persons, are only beginning to be understood87.
Follow- up of long- term effects of different HRT regi-
mens into adulthood is scarce but is much needed to
aid healthy ageing.
Birthweight. Complications at conception or in early
pregnancy and reduced fetal growth have long been
associated with atypical male genital development88
and male subfertility89. Cryptorchidism occurs with
increased frequency in preterm infants and infants
born small for gestational age; the odds ratio for hav-
ing hypospadias when born small for gestational age is
4.34 (REF.90). Conversely, in men with a clinical picture
of partial androgen insensitivity syndrome (PAIS), a
mutation in the androgen receptor is more likely if
birthweight is within the normal range than if birth-
weight is outside the normal range91. Presently, it is
unclear whether intrauterine growth restriction con-
tributes to the development of hypospadias or whether
both conditions result from a common underlying
aetiology, but androgens perse do not seem to play a
notable role in prenatal body growth. Possibly other,
so- far unidentified, factors regulate differentiation
and development of the urethra as well as prenatal
growth91,92.
Associated congenital anomalies. Some forms of DSDs
are intrinsically associated with developmental defects
affecting other organ systems, reflecting the impor-
tance of many DSD- related genes, mostly those that
encode transcription factors, in extragonadal embry-
onic development. Congenital heart defects are seen
in individuals with 46,XY DSD who have GATA4
and FOG2 (also known as ZFPM2) mutations93,94.
Cardiovascular pathology in men and women with
45,X/46,XY DSD is similar to that in women with
Turner syndrome, irrespective of the clinical pheno-
type95. Coding and structural variations in SOX9 or
some of its regulatory regions can cause, apart from
XX or XY DSD, a severe skeletal condition known
as campomelic dysplasia32. Skeletal, as well as renal,
involvement is common in MRKH syndrome96. The
Denys–Drash, Frasier and the Wilms tumour, aniridia,
genitourinary malformations, mental retardation
(WAGR) syndromes, all three of which are caused
by mutations and structural variations in WT1, are
associated with severe kidney disorders and end-
stage renal failure97,98. Upper urinary tract and kidney
abnormalities are sporadically reported in hypospa-
dias and androgen insensitivity syndrome6; however,
the long- term outcome of these conditions with regard
to kidney function is largely unknown.
Mutations in SF1 (also known as NR5A1) were
first identified in individuals with 46,XY DSD with
combined adrenal and gonadal defects99 but have
subsequently been observed in individuals with XX or
XY karyotypes with a broad range of isolated gonadal
or reproductive phenotypes. We currently do not know
whether adrenal function can deteriorate in these per-
sons over time. Sf1 has also been implicated in murine
spleen development, and in 2014 and 2016, asplenia
and/or hyposplenia was reported in some individuals
with SF1 mutations with undetermined functional
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ConSenSuS Statement

consequences100,101. The FOXL2 and RSPO1 genes
are, apart from their role in ovarian development and
maintenance, involved in developmental conditions
affecting the eye (such as blepharophimosis, ptosis
and epicanthus inversus syndrome) and skin (such as
palmoplantar hyperkeratosis and a predisposition for
squamous cell carcinoma)102,103.
Childhood and adolescent growth. Children with
45,X/46,XY karyotypes are at high risk of adult short
stature, similar to girls with Turner syndrome, irrespec-
tive of growth hormone therapy104,105. The contribution
of the sex chromosomes or the postnatal gonadotropin
surge to growth and final height is still largely unknown.
In addition, the nature of many DSD conditions, the
absence of sex steroids in late childhood and/or
the timing of puberty induction can alter typical growth
patterns106. Therefore, anthropometric data supply useful
information in the assessment of individuals of all ages
with a DSD.
Bone mineralization and osteoporosis. To date, there
has not been a systematic documentation of bone
development in children and adolescents who have a
DSD; however, decreased BMD is a common feature
in adults with a DSD. Important factors that determine
outcome with regard to bone strength are a late diagno-
sis, the type and severity of hormone deficiencies, the
duration and doses of HRT, vitamin D status, physical
activity, concomitant diseases, other medication and/or
medications and heredity107.
Women with 46,XX disorders of ovarian development
or maintenance have a marked decrease in BMD of the
lumbar spine and femoral neck108. Decreased BMD has
also been reported in up to 70% of women with CAH
aged 30 years or older86,109. In this condition, compro-
mised bone health is related not to the disease perse but
to lifelong corticosteroid replacement therapy110. Only
a handful of small- scale studies have investigated bone
health in individuals with 46,XY DSD. Women with
the complete form of androgen insensitivity syndrome
(CAIS) who had gonadectomy have a notable decrease
in BMD in comparison with male and female reference
values, whereas BMD seems to be less compromised in
women with CAIS who have retained testes111,112. Both the
lack of androgenic effects at the bone level and subnormal
oestrogen levels contribute to reduced bone health110,113.
Partially virilized women with 46,XY gonadal dysgene-
sis have a normal BMD114. No reports on fracture risk in
elderly individuals who have a DSD currently exist.
Obesity, diabetes, hypertension and cardiovascular dis-
eases. Individuals who have a sex chromosome DSD are
at increased risk of autoimmune disorders (such as type 1
diabetes mellitus and autoimmune thyroid disease), met-
abolic disturbances and type 2 diabetes mellitus115–117.
The prevalence of these conditions in men and women
with 46,XY DSD is poorly documented. Increased prev-
alence of obesity, insulin resistance and lipid abnormal-
ities has been reported in women with CAIS, possibly
due to loss of androgen receptor signalling118. Although
genetically engineered Sf1-knockout mice (Sf1−/−) have
increased vulnerability to develop obesity119, current
clinical data do not support an association between
SF1 mutations and obesity in humans120.
Metabolic disturbances are expected in women with
46,XX DSD who have a virilizing condition. Treatment-
naive and corticosteroid- treated adult women with CAH
have increased BMI, insulin resistance and higher blood
levels of glucose following an oral glucose tolerance test than
healthy controls121. High glucocorticoid doses correlate
positively with obesity in CAH adults86,109. The prevalence
of the metabolic syndrome is not well defined in other DSD
groups. Of note, individuals who receive HRT might be
vulnerable to metabolic disturbances, and clinicians should
screen these patients accordingly. Obesity can contribute
to the development of hypertension and cardiovascular
diseases122. Increased blood pressure is an int rinsic feature
of some forms of CAH, such as 11β- hydroxylase defi-
ciency, and in 17α- hydroxylase/17,20-lyase deficiency123.
Risk for gonadal germ cell cancer
Patient age
Androgen exposure
Time
Risk for
g
onadal
g
erm cell cancer
a
b
GCNIS Gonadoblastoma
Maturation delay of germ
cells
Testicular dysgenesis Undifferentiated gonadal
tissue
Gonadal differentiation
and gonadal function
Fig. 3 | Factors influencing germ cell cancer risk in individuals with 46,XY or
45,X/46,XY DSD. a | Testicular germ cell cancers in the general male population
have a peak incidence in late adolescence and early adulthood, as represented by
the incidence projection curve (solid pink line), possibly related to the rise in androgen
exposure from puberty onwards (pink dashed line, representing this hypothetical
relation); this age distribution seems to be similar in individuals who have a
difference of sex development (DSD). b | The risk of gonadal germ cell cancer in
individuals with a 46,XY or 45,X/46,XY DSD is related to the degree of differentiation
(or ‘testicularization’) of the gonads, which can be derived from histopathological and
immunohistochemical characteristics, such as the overall morphological aspect,
maturational disturbances of the germ cells, inappropriate presence of pluripotent
germ cells and impaired Sertoli or granulosa cell differentiation. Germ cell neoplasia
insitu is the expected precursor lesion in gonads with testicular differentiation;
gonadoblastoma is typically observed in highly undifferentiated gonads. The risk is
believed to be greater in abdominal than in inguinal or scrotal gonads. Genetic
predisposition (for example, by the combined presence of testicular germ cell
cancer-related single- nucleotide polymorphisms) can further modify the risk of gonadal
germ cell cancer78,83. GCNIS, germ cell neoplasia insitu.
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Increased blood pressure can also result from fludrocorti-
sone overtreatment124,125. Whether cardiovascular function
is altered in other forms of DSDs is unclear, but detailed
assessment and follow- up of the cardiovascular system
seem important in many individuals with DSDs, especially
those on HRT.
Central nervous system involvement. An increased
prevalence of cognitive and motor disturbances and
neuropsychiatric conditions has been described in
individuals with sex chromosome aneuploidies and,
to a lesser extent, in individuals who have other forms
of sex chromosomal DSD126,127. The neural system
Genetic assessment: appropriate consultations in case of hereditary gonadal disease or susceptibility prior to conception
Genetic assessment: karyotype and investigations aimed at obtaining a molecular genetic diagnosis and determining heredity
Clinical assessment
Birth Infancy AdulthoodChildhood Adolescence
Milestones Signs and markers Focus and/or aims Specific tools Current gaps and future
developments
Milestones Signs and markers Focus and/or aims Specific tools Current gaps and future
developments
External
phenotype
• Aspects of genitalia
• Spontaneous pubertal signs
• Function and appearance
• Appropriate pubertal
development
• EMS
• Prader scale
• Tanner staging
• FGS
• Non-binary and objective
external genitalia scoring
system
Internal
genitalia
• Position and size of gonads
• Development of
Müllerian and Wolffian
structures
• Functional capacity
• Function and appearance • Orchidometer
• US
• MRI
• Laparoscopy
• New non-invasive
tools for evaluation of
gonadal function
Urological
assessment
• History
• Bladder function
• Uroflow and urodynamics
• External genitalia appearance
• Prevention of incontinence
and urinary tract infection
• LUTS
• US
• Cystourethrogram
• MRI
• DSD-specific standardized
tool to describe long-term
urogynaecological outcome
• DSD-specific standardized
tool to describe long-term
urogyanecological outcome
Sexual
assessment
• Appearance of external
genitalia and breasts
• Sensation
• Erectile function and QoSL
• Satisfactory sexual life in
non-operated and
operated patients
• DSD-specific QoSL
questionnaires
• QoSL
• Questionnaires
Gynaecological
assessment
• History
• External and internal genitalia
appearance and function
• Function and appearance • US
• MRI
• Laparoscopy
Growth
and bone
development
• Neonatal biometry and
detailed anthropometry
• Bone maturation
• Bone mass accrual
• Normal growth and
development
• Growth chart
• Skeletal age
• DXA
• pQCT
• Age-specific reference
values for bone mass
Associated
features and
diseases
• Gonadal cancers
• Involvement of other organs
and systems
• Treatment of concomitant
diseases
• X-ray
• US, CT and/or MRI
• Gonadal biopsy
• Non-invasive screening
methods for gonadal
cancers
Fertility
assessment
• History
• Folliculometry and sperm quality
• Hormonal markers
• Biopsy (number and
maturation of germ cells)
• Preservation and
enhancement of fertility
• Follow-up of the
offspring’s health
• Sperm analysis
and/or US
• ART
• Gamete and tissue
cryopreserva tion
• Further development
of ART
• Uterus transplantation
• Cell reprogramming
Biochemical assessment
Milestones Gonadal function Adrenal function Pituitary function Other organ and systems function
Psychological assessment
•QoL
• Gender
contentedness
•QoL components
• Gender dysphoria signs
•Satisfactory QoL
• (Lack of) gender
dysphoria
•QoL and
• Gender dysphoria
questionnaires
• Personal assessment
• Sexual assessment
•DSD-specific QoL
• Questionnaires
• Age-specific tool for
assessment of gender
Fig. 4 | Assessment of a patient with a DSD in the clinical practice.
Assessment of an individual with a (potential) difference of sex development
(DSD) starts prenatally , followed by age- dependent relevant assessments
throughout life. Holistic assessment includes genetic, clinical, biochemical and
psychological investigations in a wide range of specific domains (left column).
For each of these domains, defined signs and markers are available that can be
used to screen for potential problems. The use of a pre- identified set of tools
enables standardized assessment for each domain, focusing on relevant
outcomes. Current gaps and future developments are listed in the right
column. Dotted lines indicate inter-relations between the DSD patient and the
family members and/or partners; solid lines indicate inter- relations between
the different aspects of assessments according to the age of the DSD patient.
ART, assisted reproductive technology ; DXA , dual- energy X- ray
absorptiometry ; EMS, external masculinization score, FGS, Ferriman- Gallwey
score; LUTS, lower urinary tract symptoms; pQCT, peripheral quantitative CT;
QoL , quality of life; QoSL , quality of sexual life; US, ultrasonography.
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ConSenSuS Statement

remains largely unexplored in non- chromosomal
DSD. Several cases of 46,XY DSD have been associated
with sensorimotor neuropathy, suggesting a hetero-
geneous molecular genetic basis for the neurological
complications128. The X- linked α- thalassemia men-
tal retardation (ATRX) syndrome is associated with
genital abnormalities ranging from cryptorchidism to
streak gonads and female- looking external genitalia
in up to 80% of affected individuals who have a 46,XY
karyotype129. Mental retardation is an important feature
of the WAGR syndrome but not the Denys–Drash or
Frasier syndromes130.
Psychiatric morbidity, anxiety and substance abuse
are common among both women and men with
CAH131,132. Glucocorticoid abnormalities can be respon-
sible for reduced working memory in both girls and
boys with CAH133, whereas prenatal exposure to excess
androgens in females is probably related to alterations in
aggression, activity level and gender- related interests134.
The influence of prenatal dexamethasone treatment on
the fetal brain, when used to avoid intrauterine viriliza-
tion of external genitalia in pregnancies at risk of CAH,
is poorly understood. Research indicates negative effects
on working memory, even after short- term exposure lim-
ited to the first trimester, in unaffected individuals135–137.
Long- term outcome data are needed to address the
controversies around this treatment.
Hormonal and genetic data
Clinical outcome is intrinsically linked to endocrine
function and underlying genetic mechanisms. As illus-
trated in FIG.4 and Supplementary Table 1, detailed
hormonal data and molecular genetic investigations
need to be meticulously collated and archived for future
large- scale data analysis.
Assessment of psychological outcome
Psychological adjustment and psychopathology. Some
studies report increased prevalence of psychological dis-
tress, self- harm and suicidal tendencies in individuals
who have a DSD52. Known causes include experi-
encing taboo, shame or secrecy; however, living with
chronic illness and DSD- related physiological sequelae
might also contribute to increased distress35,138. Peer
support has been shown to have positive effects on
psychological well- being30. Factors related to medical
care, such as hormonal status and level of informa-
tion sharing, can hinder or facilitate acceptance of the
condition12,26. Documentation of the communication
process will ultimately enable study of the effect of
adequate (and inadequate) information and participa-
tion in decision- making on psychological adjustment
and coping.
Gender contentedness. Assessment of gender iden-
tity and gender- related behaviour in individuals
with a DSD has become a particularly sensitive topic
given evolving sociological perspectives on a histor-
ically binary framework of sex and gender. Societal
acceptance of non- stereotypic gender presentation
and non- binary gender identities has increased in the
past decade139. In a clinical setting, this has translated
into recognition of the need for nuance in assessing
gender- related presentation. For example, gender role
behaviour and/or presentation should be considered
as distinct from core gender identity, which is defined as
the basic sense of self as male and/or female and/
or other, in drawing clinical conclusions about gen-
der development140. In the most recent version of the
Diagnostic and Statistical Manual for Mental Disorders
(DSM-5)141, the diagnostic criteria for gender dys-
phoria have changed to reflect this distinction. In
contrast to past conceptualizations, in which a gen-
der non- conforming presentation could have been
diagnosed (or misdiagnosed) as gender dysphoria, a
strong desire to be another or other gender must now
be clearly demonstrated by an individual. In addition,
the new formulation includes the provision for a diag-
nosis in individuals with a DSD, in contrast to previous
editions where the presence of a DSD was considered
an exclusionary criterion.
According to the literature, the above distinction
is critical for assessing gender- related development in
DSDs. Although variance in gender role behaviour or
sexual orientation might draw clinical attention and/or
warrant provision for added psychological support, dis-
tress related to core gender identity is a more serious
matter, with the potential need for medical intervention,
such as a revised hormone replacement regime or
surgical gender reassignment139. Although there is a
growing recognition of gender and gender identity as
a continuum rather than a binary concept, the major-
ity of individuals with DSDs identify with the gender
designated at birth, that being either male or female, as
do >99% of the general population142. However, rates of
gender dysphoria, intersex, intergender identities and/
or gender change are higher in patients with DSDs than
in the general population143–151. The greater degree of
variance in gender- related development in DSDs than
in non- DSD populations is probably due to a com-
plex interaction of genes, varied exposure to sex hor-
mones in the perinatal period and again at puberty and
the psychological and/or emotional sequelae of living
with a DSD.
A holistic and patient- centred model of health care
should be sensitive to the potential for secondary distress
arising from discomfort with one’s gender. Therefore,
enquiries about an individual’s gen der experience and
gender- related contentedness are important. At the same
time, the assessment should be framed in a way that does
not stigmatize or pathologize any particular gendered
presentation. Questions can be asked in an open- ended
manner so as not to raise a ‘typical or atypical’ dichotomy.
In addition, the criterion of note with respect to poten-
tial clinical concern is the presence of distress. ‘Atypical’
presentation is very often not accompanied by distress,
and gender- related contentedness is mostly satisfac-
tory in such cases150. The aim of these questions is to
give patients and families support relevant to physical,
psychological and emotional aspects of DSDs in an
open- minded and caring environment150. A review of
psychological assessment across the lifespan addresses
the nuance and complexities of gender development
in DSDs152.
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ConSenSuS Statement

Quality of life
Optimizing quality of life is a primary goal of holistic
care and outcome- focused research. Given the rarity
of the individual conditions, most studies include a
conglomerate of diagnoses, which yields inconsistent
results and the general conclusion that DSD- related
quality of life is understudied153,154. In addition, earlier
studies report on women who have not experienced
the current patient- centred standard of care by a multi-
disciplinary team. Studies on larger series of mainly
XY DSD conditions show overall equal quality of life,
compared with the local general population, although
some studies suggest suboptimal quality of life, specif-
ically in the social and psychological, but not physical,
domains154–158. In conclusion, appropriate question-
naires should be designed for assessing quality of life in
individuals with diverse sex development, focusing on
partnership, sexuality and fertility, in addition to those
assessing physical quality of life.
Conclusions
Within the management of DSDs, many unsolved
questions remain, especially in older age groups.
The establishment of proper genotype–phenotype
correlations and addressing the identified gaps in our
current knowledge are primary tasks of future research.
To reach these goals, it is crucial that patient follow-
up continues throughout their lives in dedicated refer-
ence centres, where possible. Prospective multicentre
data collection in adults is one of the most urgent needs
given that this has been a long- neglected group with
respect to clinical research.
According to a scarce and dispersed literature, many
adults who have a DSD are probably at increased risk of
various cardiovascular, metabolic and neuropsychologi-
cal comorbidities, possibly related to the specific genetic
constitution or to current treatments. The benefits and
risks of HRT in patients with DSDs specifically are
largely unknown and need further studies.
Concerns exist with regards to the effects of delayed
genital and gonadal surgery on social acceptance, psy-
chological well- being, parent–child bonding, body image
and sexual functioning as well as the malignancy risk of
retained gonads. Studies assessing the effect of deferred
surgery on the above domains and comparing psycholog-
ical outcomes with and without surgery are underway. In
addition, insight into reasons why families might some-
times insist on having genital surgery for their child and
investment in support tools and guidance for families
and children living with atypical genitalia are urgently
needed. Meanwhile, an appropriate balance between gen-
ital surgery on the one hand and the protection of human
rights and dealing with ethical dilemmas on the other
must be found. Longitudinal studies of genital surgery
that focus on genital outcomes, and that neglect urinary
functioning, can lead to inappropriate conclusions.
The creation of multidisciplinary teams dedicated to
the management of DSD conditions worldwide poses
its own challenges. Apart from economical limitations
and practical hurdles, training of staff with respect to
the acquisition of knowledge, as well as communication
skills, is an ongoing endeavour159. Examples that outline
the role of team members as well as team responsibili-
ties are available28,160. Developing networks of peers who
have received specific training and who can be included
in the multidisciplinary team can enrich the decision-
making process with a (so far) under- represented and
much broader perspective.
Towards the aims of facilitating systematic and struc-
tured patient follow- up in parallel with accumulating
much- needed data for future DSD research, consensus
among health- care providers, researchers and service
users is crucial. To avoid selection bias in patient-
reported outcomes, we recommend a standardized,
non- binary and holistic assessment of individuals at
specific life stages and in the context of mandatory clin-
ical assessment or review. Prospective studies are best
managed in a multidisciplinary setting, including both
paediatric and adult specialists, with the aim of system-
atic, longitudinal data collection using evidence- based,
standardized assessment tools and protocols. By doing
so, critical developmental milestones and/or long- term
sequelae associated with various DSD conditions can be
captured. Rapid translation of obtained clinical research
data into evidence- based practice requires investment
in enhanced communication strategies, systems for
electronic data storage, exchange and analysis, foster-
ing a long- term vision of the organization of health-
care structures and improved professional and public
understanding of the needs and actions that drive pro-
gress on this matter. Large- scale networks that are cur-
rently being formed, such as Endo- ERN in Europe and
the DSD Translational Research Network in the United
States, are promising developments in this direction. At
the root of the endeavour, holistic health care and clini-
cal research should always be performed in accordance
with each patient’s expectations and with sincere respect
for their integrity.
Published online xx xx xxxx
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Acknowledgements
The authors thank the members of the COST Action BM1303
working group 1: C. Bouvattier, Paediatric Endocrinology,
Bicêtre Hospital, Paris, France, and National Reference Centre
for DSDs, Paris Sud University, Paris, France; A. Gawlik,
Department of Paediatrics and Paediatric Endocrinology,
School of Medicine in Katowice, Medical University of Silesia,
Katowice, Poland; S. Hannema, Sophia Children’s Hospital,
Erasmus University Medical Centre, Rotterdam, Netherlands,
and Department of Paediatrics, Leiden University Medical
Centre, Leiden, Netherlands; D. Hebenstreit, Medical University
of Vienna, Vienna, Austria; K. Kapczuk, Division of Gynecology,
Poznan University of Medical Sciences, Poznan, Poland; Z.
Kolesinska, Department of Paediatric Endocrinology and
Rheumatology, Poznan University of Medical Sciences, Poznan,
Poland; M. Lindhardt Johansen, Department of Growth and
Reproduction, Rigshospitalet, University of Copenhagen,
Copenhagen, Denmark, and International Center for Research
and Research Training in Endocrine Disruption of Male
Reproduction and Child Health, Rigshospitalet, University of
Copenhagen, Copenhagen, Denmark; M. Niedziela,
Department of Paediatric Endocrinology and Rheumatology,
Poznan University of Medical Sciences, Poznan, Poland; S.
Riedl, St. Anna Children’s Hospital, Paediatric Department,
Department of Paediatric Pulmology, Allergology and
Endocrinology, Medical University of Vienna, Vienna, Austria; V.
Tillmann, Children’s Clinic of Tartu University Hospital,
University of Tartu, Tartu, Estonia; S. vander Straaten,
Department of Paediatric Endocrinology, Ghent University
Hospital, University of Ghent, Ghent, Belgium; R. Veijola,
Department of Pediatrics, PEDEGO Research Unit, Medical
Research Center, Oulu University Hospital and University of
Oulu, Oulu, Finland.
Author contributions
M.C., A.N., R.R., C.F., B.K., M.B., A.S., K.S. and V.P. wrote the
article. All authors researched data for the article, made
substantial contributions to discussion of the content and
reviewed and/or edited the manuscript before submission.
Competing interests
This article is based upon work from the European Cooperation
in Science and Technology (COST) Action DSDnet, supported
by COST. M.C. holds a senior clinical investigator grant from
the Research Foundation Flanders (Belgium). A.N. holds a
senior investigator grant from the Karolinska Institutet and the
Stockholm County Council (Sweden). C.F. is supported by the
Swiss National Science Foundation (grant number 320030-
146127). B.K. is supported by a grant from the European
Union Seventh Framework Programme (FP7/2007-2013)
grant number 305373.
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RELATED LINKS
Action DSDnet: http://www.dsdnet.eu
dsd- LIFE: http://www.dsd- life.eu
DSD Translational Research Network: https://dsdtrn.
genetics.ucla.edu
Endo- ERN: https://endo- ern.eu
European Commission’s Action Plan for Rare Diseases:
https://ec.europa.eu/health/rare_diseases
I- CAH Registry: https://registry.i- cah.org
I- DSD Registry: https://www.i- dsd.org
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ConSenSuS Statement