Abstract
The term DSD (Disorders/Differences of Sex Development) includes many rare
genetic diagnoses that are associated with an atypical course of sex development
or an abnormal sex chromosome composition.
In addition to physical and medical consequences, the psychosocial and social
consequences are significant for part of the individuals with a DSD diagnosis. Care
is therefore centered in expertise centers with a multidisciplinary team. Together
with (the caregivers, usually the parents of) the person who has a form of DSD, this
care is adapted as optimally as possible to the interests, capabilities and needs of
the person concerned, in a complex and ever-changing social landscape.
Genetic education and genetic testing have become increasingly important due
to increasing possibilities and knowledge. This thesis describes various studies
conducted in the context of DSD.
Chapter 1 provides an introduction to sex development and the most important
genes and molecular pathways involved. At the end of the chapter, the purpose
of the studies and the questions we try to answer in this dissertation are further
explained.
Chapter 2 lists a number of points where care can be further improved for families
in which a form of DSD may occur. Communication with and education of colleagues
with less experience remains important. The authors see the need for a national
prenatal policy, because it should not make any difference to the information that
a pregnant woman receives and the subsequent care, where a pregnant woman is
told that her unborn child probably has an atypical genital.
In Chapter 3 we discuss in more detail the policy we implement at Erasmus MC if a
pregnant woman is referred with a suspected atypical genital on the child’s prenatal
ultrasound. A study among more than 50 pregnant women and their partners
shows a high turnout for information about the options for genetic diagnosis during
pregnancy and the possible trajectory after birth. This group appears to be able to
choose whether or not they want invasive testing after receiving the information.
The terminology is sensitive and ‘atypical’ is currently preferred to ‘anomaly’ for the
description of the aspect of the genital. However, avoiding the word ‘abnormality’
should not lead to refraining from offering extensive diagnostics and counseling as
is common with other structural ultrasound abnormalities.
Chapter 4 describes a special case of an adult man who turned out to have a rare,
chromosomal form of DSD. The analysis of various genetic tests shows that this
209
Summary
form of DSD, which is called tetragametic chimerism, is easily recognizable through
regular array examination, especially when looking at different tissues. Although
there was abnormal gonadal development, this is not a form of DSD that is visible at
birth and can go unnoticed for life if there are no complications. Maintaining fertility
is not easy in this situation, but is strived for.
Chapter 5 summarizes the epigenetics of the early stages of germ cell tumors. The
risk of these tumors is increased with a number of specific DSD diagnoses and is
therefore important when discussing the options in the treatment process with
careful consideration of the balance between preventing malignant transformation
and preserving hormone production and fertility.
Finally, Chapter 6 describes a pilot study of 16 XY patients with proximal hypospadias,
half of whom had low birth weight. We used a technique developed at Erasmus
MC to demonstrate genome-wide regions with differential DNA methylation
(DMRs). Despite the strong suspicion that epigenetic regulation (e.g. different DNA
methylation) could play a role in the development of proximal hypospadias, we
could not clearly demonstrate a different methylation pattern, even in children
with a low birth weight. Even so, it cannot be ruled out that this regulation plays a
role in the development of a proximal hypospadias or other form of DSD. Altered
methylation of the promoter region of a gene involved in sex development was
found in a number of patients, but the significance of this is still unclear. A male
patient with testicular DSD was also analyzed with this technique and showed
methylation partially consistent with female XX controls but a possible cause of
the DSD was not found.
The discussion in Chapter 7 is about the importance of implementing prenatal
diagnosis when DSD is suspected, genetic reanalysis with state of the art techniques
and reclassification of variants and functional research of found variants of unknown
clinical significance now, but also in the future. Attention is also needed for the gap
between, on the one hand, shared decision making, in which care is coordinated
with the patient and/or parents, and personalized medicine that are standard in
modern medicine, and on the other hand, the demand for a legal ban on genital
surgery in children by social groups. New knowledge about the involvement of other
genetic mechanisms and new possibilities for researching these, such as epigenetics
or variations in regulatory areas, the non-coding part of the DNA, etc., will provide
more knowledge of sexual development, which may lead to opportunities to improve
clinical care.
genetic diagnoses that are associated with an atypical course of sex development
or an abnormal sex chromosome composition.
In addition to physical and medical consequences, the psychosocial and social
consequences are significant for part of the individuals with a DSD diagnosis. Care
is therefore centered in expertise centers with a multidisciplinary team. Together
with (the caregivers, usually the parents of) the person who has a form of DSD, this
care is adapted as optimally as possible to the interests, capabilities and needs of
the person concerned, in a complex and ever-changing social landscape.
Genetic education and genetic testing have become increasingly important due
to increasing possibilities and knowledge. This thesis describes various studies
conducted in the context of DSD.
Chapter 1 provides an introduction to sex development and the most important
genes and molecular pathways involved. At the end of the chapter, the purpose
of the studies and the questions we try to answer in this dissertation are further
explained.
Chapter 2 lists a number of points where care can be further improved for families
in which a form of DSD may occur. Communication with and education of colleagues
with less experience remains important. The authors see the need for a national
prenatal policy, because it should not make any difference to the information that
a pregnant woman receives and the subsequent care, where a pregnant woman is
told that her unborn child probably has an atypical genital.
In Chapter 3 we discuss in more detail the policy we implement at Erasmus MC if a
pregnant woman is referred with a suspected atypical genital on the child’s prenatal
ultrasound. A study among more than 50 pregnant women and their partners
shows a high turnout for information about the options for genetic diagnosis during
pregnancy and the possible trajectory after birth. This group appears to be able to
choose whether or not they want invasive testing after receiving the information.
The terminology is sensitive and ‘atypical’ is currently preferred to ‘anomaly’ for the
description of the aspect of the genital. However, avoiding the word ‘abnormality’
should not lead to refraining from offering extensive diagnostics and counseling as
is common with other structural ultrasound abnormalities.
Chapter 4 describes a special case of an adult man who turned out to have a rare,
chromosomal form of DSD. The analysis of various genetic tests shows that this
209
Summary
form of DSD, which is called tetragametic chimerism, is easily recognizable through
regular array examination, especially when looking at different tissues. Although
there was abnormal gonadal development, this is not a form of DSD that is visible at
birth and can go unnoticed for life if there are no complications. Maintaining fertility
is not easy in this situation, but is strived for.
Chapter 5 summarizes the epigenetics of the early stages of germ cell tumors. The
risk of these tumors is increased with a number of specific DSD diagnoses and is
therefore important when discussing the options in the treatment process with
careful consideration of the balance between preventing malignant transformation
and preserving hormone production and fertility.
Finally, Chapter 6 describes a pilot study of 16 XY patients with proximal hypospadias,
half of whom had low birth weight. We used a technique developed at Erasmus
MC to demonstrate genome-wide regions with differential DNA methylation
(DMRs). Despite the strong suspicion that epigenetic regulation (e.g. different DNA
methylation) could play a role in the development of proximal hypospadias, we
could not clearly demonstrate a different methylation pattern, even in children
with a low birth weight. Even so, it cannot be ruled out that this regulation plays a
role in the development of a proximal hypospadias or other form of DSD. Altered
methylation of the promoter region of a gene involved in sex development was
found in a number of patients, but the significance of this is still unclear. A male
patient with testicular DSD was also analyzed with this technique and showed
methylation partially consistent with female XX controls but a possible cause of
the DSD was not found.
The discussion in Chapter 7 is about the importance of implementing prenatal
diagnosis when DSD is suspected, genetic reanalysis with state of the art techniques
and reclassification of variants and functional research of found variants of unknown
clinical significance now, but also in the future. Attention is also needed for the gap
between, on the one hand, shared decision making, in which care is coordinated
with the patient and/or parents, and personalized medicine that are standard in
modern medicine, and on the other hand, the demand for a legal ban on genital
surgery in children by social groups. New knowledge about the involvement of other
genetic mechanisms and new possibilities for researching these, such as epigenetics
or variations in regulatory areas, the non-coding part of the DNA, etc., will provide
more knowledge of sexual development, which may lead to opportunities to improve
clinical care.
Original language | English |
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Awarding Institution |
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Supervisors/Advisors |
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Award date | 15 Jan 2025 |
Place of Publication | Rotterdam |
Print ISBNs | 978-94-6506-642-4 |
Publication status | Published - 15 Jan 2025 |