DDX3X syndrome

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What is DDX3X syndrome and how is it caused?
DDX3X syndrome is a genetic condition that occurs in females, and very rarely in
males with developmental delay and/or intellectual disability. The first individuals
with this condition were reported in 2015.
DDX3X syndrome occurs when one of the two copies of the DDX3X gene has lost its
expected function. This is caused by a change to the gene sequence, known as a variant.
Genes are instructions which have important roles in our growth and development.
They are made of DNA and are incorporated into organised structures called
chromosomes. Chromosomes therefore contain our genetic information. The DDX3X
gene is located on the X chromosome. Chromosomes are located in our cells, the
building blocks of our bodies.
Although DDX3X syndrome occurs primarily in females, currently (2021) a few
families are known in which males have a variant in the DDX3X gene and have
intellectual disability. This condition presents differently to the DDX3X syndrome in
females. The inheritance pattern can also be different. In this guide we focus on
DDX3X syndrome as it has been found in females but have added a section for the
most recent observations made in boys with a DDX3X variant on page 3.
DDX3X is an emerging syndrome, so what we know about its effects will increase a
lot in the next few years.

Most girls with DDX3X syndrome have:

Developmental delay (DD) or intellectual disability (ID)
Behaviour difficulties, including autism spectrum disorder (ASD)
and ADHD (attention deficit hyperactivity disorder)
Low muscle tone (hypotonia)
Feeding difficulties
Joint laxity and/or scoliosis
Girls and women with DDX3X syndrome have different medical problems and
varying degrees of developmental delay. It is currently not fully understood what
causes these differences in severity and the associated difficulties or symptoms.

 Having had contact with lots of other DDX3X parents through



the Facebook page, I’ve come to realise that it seems impossible

to predict the developmental path of these children as they are
all so different. Although there are common traits, some of the
children are much more severely affected than others. 

How many people have this condition?

Almost 150 females with DDX3X syndrome have been described
in the medical literature, and 10 males (2021). However, more
16 years people are known to have DDX3X syndrome but have not been
reported in the medical literature. It is thought that 1-3% of
intellectual disability in females is caused by DDX3X variants. With the increasing use
of the latest gene sequencing technology, it is expected that many more children and
adults will be diagnosed with this condition in the next few years.
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Boys with DDX3X
So far (2021), ten males from different families have been identified as having a
DDX3X-related neurodevelopmental disorder. Although there is a lot less information
available than for females, the following observations have been made:
All reported individuals have intellectual disability or developmental delay,
ranging from mild to severe
Many, but not all boys have a small head circumference (microcephaly)
Similarly to girls, the following features have been observed in boys:
behavioral difficulties, spasticity, tremor, hypotonia, vision problems,
congenital heart disease, and delayed puberty
Brain scans have shown abnormalities in the bundle of nerve fibres (corpus callosum)
that connects the two halves of the brain, which may lead to loss of communication
between the two brain parts. Enlarged ventricles (ventriculomegaly) and white matter
abnormalities associated with slower speech processing, have also been identified.
Why did this happen?
When children are conceived, genetic material is copied, with
one half coming from the egg and one half from the sperm.
The biological copying method is not perfect and occasionally
random rare changes occur in the genetic code of children
that are not seen in the DNA of their parents, this is known as
de novo. These types of change happen naturally and are not
due to anything anybody did. A spontaneous change in the
DDX3X gene cannot be predicted or prevented. No
2 years
environmental, dietary or lifestyle factors are known to cause
a spontaneous change in this gene. No one is to blame when they occur and nobody is
at fault.
In all females with DDX3X syndrome reported in the medical literature so far (2021)
the DNA change in the DDX3X gene occurred de novo. For boys, some have been
found to have a de novo variant, and others have inherited a DDX3X variant from an
unaffected mother.
Can it happen again?
The risk of having another child affected by a rare gene disorder depends on the
genetic code of the parents. For DDX3X syndrome, where a parent does not carry the
same DDX3X change as their child, the chances of having another child with DDX3X
syndrome are very low (estimated at less than 1%). Nonetheless, there is a very small
chance that some of the egg cells of the mother or some of the sperm cells of the
father could carry the change in the DDX3X gene. This is called germline mosaicism.
It means that parents who are not found to be carriers of the same DDX3X change as
their child on a blood test still have a very small chance of having another child with a
DDX3X variant. In an individual with a diagnosis of a DDX3X-related disorder, there is
a 1 in 2 chance of passing the genetic variant on to their children.
The risk for healthy brothers and sisters of having a child with DDX3X syndrome is not
increased and is the same as for anyone else in the population. However, each family
situation is different and a clinical geneticist can give you specific advice for your
family and, if applicable, discuss options for testing regarding future pregnancies.
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Can DDX3X related conditions be cured?
There are no cures since the effects of the genetic change take place during a baby's
formation and development. However, knowing the diagnosis means that
appropriate monitoring and treatment can be put in place for each child.
Managing a DDX3X related condition
Children with a DDX3X related condition should be followed up by a paediatrician to
monitor growth, development, speech and behaviour. Depending on the medical
problems that are present in each individual, the paediatrician can provide parents
with the best help in the form of physio-, occupational, behaviour and speech
therapies.
Development
Growth
Most babies are a normal weight and length at birth. Around one third of babies
have a small head circumference (microcephaly). Girls’ height and weight often
remain normal as they are growing up. However, being underweight is more
common in girls with DDX3X syndrome compared with other girls of the same age.
Speech
Most girls and women with DDX3X syndrome have speech difficulties and/or a
delayed development of speech and language.

Unique’s experience is that

girls said their first words at 2
 M can repeat words or phrases but it’s


extremely difficult for her to use language

-5 years. However, speech is
not possible for some, and all to express herself. But she loves to
girls rely to a greater or communicate one to one. 16 years
lesser extent on other means  A is working hard at using a


of communicating. These can communication aid to speak, and is doing

include gesture, sound well with 2-3 word sentences. It is lovely to
approximations, pictures, hear her enthuse about her favourite things
signing, and electronic – music, trains, sharks, her dog.  16 years
communication devices.

 When A began mainstream school she was about a year to 18 months



behind the other kids, but this increases year on year and she's now more
like 3 years behind. Though several years below the other children, she has
coped in a mainstream primary school with full time 1:1 support, although
she will certainly need to attend a special school at secondary level. She has
memory problems: working memory, short term memory and general
recall.  9 years
P’s school report shows a fairly spiky profile of development.  16 years

Learning
All girls with DDX3X syndrome who we currently know about have some degree of
developmental delay or intellectual disability. The range of difficulties are very
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broad, varying from mild to severe. So far, most of
the girls we know about have needed special
education. Some girls go to mainstream primary
schools, but most switch to specialised schooling in
the secondary school years. Some have a mild
intellectual disability, and are able to communicate,
learn many skills and have independence. Others
have a severe intellectual disability, have major
difficulties with communicating and need a lot of
supervision and support.
Families say that any behaviour difficulties are
easily provoked by fear and anxiety or by being in
the wrong environment. Many families also say
their daughter has sensory processing difficulties,
meaning that their nervous system fails to receive
and/or respond appropriately to incoming
messages. They point to their daughters’ happy and
affectionate nature, empathy and love of music.  Very much a beautiful


 Behaviour problems is an unfortunate term used


young woman.  16 years
to umbrella a lot of traits. 


 A happy, perky nature  When she was little we had terrible
 

is a common trait.  problems with her pulling hair. Sometimes she

 A charming child.

was aggressive and quick to anger, mostly due to
Naturally cheerful and stoic, frustration, feeling thwarted or problems with
which is amazing when you transition. Fear or worry can also lead her to
consider the challenges she instinctively lash out.  9 years
faces every day. She’s now  There are only very brief moments of aggression


also cheeky, funny, when she is really struggling in an overwhelming

understands humour and is situation. But she is very aware and sorry once the
humorous herself.  9 years moment has passed. This is her reacting to the
 Always happy, smiles a lot,

environment not being right for her as opposed to a
and has a great sense of fun problem with her.  16 years
and slapstick humour.   M requires a one to one supportive loving care


11 years with a lot of reassurance and stability, the ability and

 A happy girl with a passion
 freedom to regulate herself regularly and the option
for music and trying to to be at the edge as opposed to being in the middle
dance. She loves her cocker of a group.  16 years
spaniel. 16 years  Diagnosed as autistic, but happy and smiley. 


16 years

Sensory difficulties and anxiety

Families often point to their daughter’s happy, friendly and caring nature. If any
difficulties do occur, they can include autistic features, some level of hyperactivity,
difficulty regulating emotions, and sometimes aggression. There is a large
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spectrum of these behaviours, with some children
experiencing a few difficulties in social functioning
versus severe difficulties in others.
Some girls with DDX3X syndrome may experience
increased anxiety, triggered by uncertainty about
future events, specific objects or situations, and/or
sensory sensitivity. Anxiety in DDX3X syndrome may
be more common than in other genetic disorders.
Sometimes, responses to distress can include self-
injurious behaviours such as self-hitting, biting,
head-banging, or skin-picking and scratching.

 She very much enjoys sport and



dog training. P is also very keen on

indoor climbing on climbing walls. A
9 years
real outdoor girl.  16 years
Medical concerns
Low muscle tone, joints and movement disorders
Most babies with DDX3X syndrome have low muscle tone (hypotonia) at birth. This
means that the baby is floppy. Low muscle tone may persist throughout childhood.
Some girls and boys develop increased muscle tone (spasticity) in the legs. An
unusual gait is seen in some children and adults, mainly a stiff-legged and/or wide
based gait, where they walk with their feet wide apart.
Joint bendiness (hyperlaxity) is a feature that is commonly seen in girls with DDX3X
syndrome. In addition, most girls with DDX3X syndrome experience difficulties with
balance and coordination.
Unique’s experience is that babies learned to sit unsupported at 11-18 months and
to walk at 23 months-5 years. This may not be possible for all. Low muscle tone
generally improves, but may not disappear altogether. Families attribute persisting
movement difficulties to a variety of causes: proprioception (not knowing where they
are in space) and crossing the midline (bilateral integration); motor control; motor
planning; and musculoskeletal issues (in-turned hips).

 She has always ‘flapped’ and bounced up and down when excited.


She currently licks her chin intermittently.  9 years

 Quite recently a big increase in involuntary movements, jerks and tics as


well as intermittent difficulties with motor control. She is unable at times to

complete a task, such as picking up a cup or making the next step. This can
even effect chewing co-ordination.  16 years

Brain
In about half of the girls with DDX3X syndrome some abnormalities are seen on a
brain MRI scan. Brain anomalies have also been found in MRI scans of boys with a
DDX3X variant. These can be diverse, but include underdevelopment of the corpus
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callosum (the band of nerve fibres between the two sides of the brain), enlarged
ventricles (the ventricles are the fluid-filled parts of the brain) and disorders
affecting the formation of the grey matter in the brain’s outer layer (cortex).
Seizures
Some girls with DDX3X syndrome do not develop seizures but others do.
Hearing & vision
Some, but not all girls with DDX3X syndrome have hearing or vision difficulties.
Hearing problems may be conductive (concerning the outer and mid-ear),
sensorineural (concerning the cochlea or the neural pathway leading to the auditory
cortex) or both. At present little is known about age of onset or progression of
hearing loss in children with a DDX3X variant.
Vision
Unique’s experience is that vision problems can occur. Those reported include:
immature visual perception; squint (strabismus); long or short sight; astigmatism,
causing some distortion or blurring of vision; nystagmus (uncontrolled eye
movement); palsy of the optic nerve with difficulty coordinating the movement of
both eyes and the possibility of intermittent interruptions in vision; and CVI (cortical
visual impairment) causing difficulties with tracking. Vision problems were reported
in one in 3 girls or women in a large study of DDX3X syndrome.

Feeding Sleep
Families have met a variety of Families commonly face sleep
feeding issues. They include: problems, particularly in the first two
Weak, ineffective sucking and slow years.
feeding as a baby.  Under a year she never slept longer

Chewing and swallowing difficulties. than 3 hours at a time, day or night. As
Severe reflux and eosinophilic she grew, she could not self settle and
oesophagitis, an inflammation of the needed constant reassurance. She has
oesophagus (food passage). woken every night since birth with
Difficulties using a knife and fork differing success in getting her back to
together due to problems integrating sleep or into her own bed. She can now
actions on both sides of the body. self settle at bedtime, but still wakes
Slow gut transit time. occasionally.  11 years
Overeating and difficulty sensing
when full.
Short concentration span and
Constipation, responding to medication. hyperactivity
 Sensory processing difficulties

Toilet training
(sensory seeking but also sensory
 When she was younger she had a lot of

sensitive to aural and visual stimulation)
UTIs, put down to her toilet training affect her attention and focusing. 
difficulties and being wet a lot.  9 years
 She toilet trained in the day at 8 years.

 When younger she was hyperactive

We are still working on being dry at night, with a short attention span. Now she is
and are to try Desmopressin much calmer and still has a short but
(a medicine that reduces the amount better attention span.  16 years
of urine).  11 years
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DDX3X Support UK is a UK based information and support group for patients and
families affected by the DDX3X gene mutation https://ddx3xsupportuk.co.uk
DDX3X Foundation and registry (US based)
http://ddx3x.org
DDX3X Facebook page
www.facebook.com/groups/geneddx3x
DDX3X UK Facebook page
https://www.facebook.com/groups/DDX3X

This guide was made possible by contributions from:

Fonds NutsOhra, Erfocentrum, VGnetwerken and VKGN in the Netherlands.
Unique lists external message boards and websites in order to be helpful to families looking for
information and support. This does not imply that we endorse their content or have any responsibility
for it.
This information guide is not a substitute for personal medical advice. Families should consult a
medically qualified clinician in all matters relating to genetic diagnosis, management and health.
Information on genetic changes is a very fast-moving field and while the information in this guide is
believed to be the best available at the time of publication, some facts may later change. DDX3X is an
emerging syndrome, so what we know about its effects will increase a lot in the next few years and
Unique will do its best to regularly update this guide.
The text was written by Dr Lot Snijders Blok, MSc, MD, Department of Human Genetics, and Dr
Tjitske Kleefstra, Clinical Geneticist, Nijmegen Medical Center, Netherlands, and the leaflet was
compiled by Unique with the participation of Dr Laura van Dussen, MD (Erfocentrum), Marloes
Brouns-van Engelen (Erfocentrum), Professor Conny van Ravenswaaij-Arts (UMC Groningen) and
Mieke van Leeuwen (VGnetwerken). With special thanks to Annet van Betuw (VanBetuwAdvies),
Marja de Kinderen (PROK Project management and training), Joyce Schaper (Chromosome
Foundation) and Sarah Wynn, BSc(Hons) PhD DIC (Unique).This guide was updated in 2021 by Dr
Anna Kolesnik-Taylor, Dr Kate Baker and Elise Ng-Cordell (MRC Cognition and Brain Sciences Unit,
University of Cambridge) together with Unique (AP). 2016 Version 1 (PM); v1.1 (CA); v1.2 (CA); v2 (AP)
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