Introduction

Rare chromosome disorders, as their name suggest, are a somewhat nebulous

category of diseases arising from chromosomal abnormalities that are deemed to
be extremely uncommon. The quantifiable basis for being classified as rare is
based on a definition provided by the National Organisation for Rare Diseases, an
American based non for profit that provides support to those diagnosed with a
rare chromosome disorder and their families. The definition classifies any disease
or disorder affecting less than 200000 people (less than 0.0006%) within the US
population as rare1. While the prevalence of certain disorders will differ from
country to country, there is currently no Australian equivalent or agreed
international standard definition, which in itself is evident of the lack of
awareness and the potential obstacles that may arise for those with a rare
chromosomal disorder seeking medical assistance in countries like Australia. This
medical assistance would consist of financial assistance as well as the provision
of resources to aid long-term management as there is no curative treatment for
rare chromosome disorders.
Chromosome 5 trisomy disorders are particularly uncommon, with insufficient
research data and epidemiological studies conducted and only slightly over 40
known cases worldwide. These disorders come in two forms, chromosome 5p
trisomy and chromosome 5q trisomy, where p represents the long arm of the
chromosome and q the shorter arm. Although presenting differently in the
clinical context in terms of physical and facial features, both forms result in
significant global developmental delay, defined as a delay in achieving
developmental milestones in more than one of the following categories: motor
skills, speech and language, cognition as well as self-care and social skills. Global
developmental delay in those with chromosomal disorders is essentially
synonymous with intellectual disability, which affects approximately 4% of all
Australian children aged from 0-14 years 2.
The following is a case study on a girl with duplications involving both arms of
chromosome 5, resulting in both severe global developmental delay as well as
numerous issues with her respiratory health and physical development. Beyond
her medical history, there will be discussion on the efficacy of certain
management as well as some of the challenges a child with global
developmental delay secondary to a rare chromosome disorder might face. For
the sake of confidentiality, the pseudonym Jane will be used throughout.

Janes History
Jane is a nine year old girl with a rare chromosomal disorder involving
duplications of two segments of chromosome five (segments 5p13.1-5p14.1 and
5q11.1-5q11.2), which is the only documented case in the world. She lives in a
1 Global Genes. R.A.R.E List. http://globalgenes.org/rarelist/ (accessed
22/02/2015)
2 Australian Bureau of Statistics. 2012 Survey of Disability, Ageing and Carers,
2012

loving and nurturing environment with her mother, father and seven year old
brother in northwest Sydney.
This was her mothers first pregnancy and Janes gestation had multiple
complications. Her mother had recurrent asthma as well as repeated respiratory
tract infections throughout the pregnancy, as well as a diagnosis of
polyhydramnios which partially accounted for the 30kgs of weight gain. Research
indicates that the major risk factors for polyhydramnios can be divided into two
categories, either due to maternal health issues or the inability for the fetus to
swallow the amniotic fluid3. The former includes rhesus incompatibility, diabetes
mellitus, intra-uterine infections or the presence of a benign mass at the
placenta (chorioangioma). However, Janes mother denied any medical history of
any such conditions (though mentioned having been diagnosed with polycystic
ovarian syndrome) and confirmed that she was screened for gestational diabetes
due to her significant weight gain but was cleared. As such it is possible that the
polyhydramnios may have resulted from Janes chromosomal abnormalities,
which became apparent at her birth.
Neither Janes mother nor her father reported having any previous family history
of chromosomal abnormalities and as such no genetic testing was done.
Ultrasound imaging became a weekly routine closer to the end of the pregnancy
with no abnormalities or malformations evident, apart from a large head
circumference that, in conjunction with the polyhydramnios, resulted in the
decision to perform caesarean section at 38 weeks gestation.
At birth Jane was severely cyanosed, in respiratory distress (which was further
evident from recessive breathing) and hypotonic, requiring resuscitation.
Although initially resuscitated, she became cyanotic soon after attempted breast
feeding and was transferred to the Special Care nursery. On examination, her
respiratory difficulties had persisted as well as her hypertonia. A systolic ejection
heart murmur was also present over the pulmonary valve region, however the
atrial septal defect that caused it was mild and as expected by the physicians
responsible for Janes care, self-resolved over time. Further investigations by the
hospital staff cleared her of hydrocephalus, but the karyotyping from initial blood
investigations provided results that there was extra material on chromosome
5.
She received nutrition through a nasogastric tube initially, followed by sucking on
a specially designed cross cut teat as she was not capable of regular breast
feeding. After two weeks she was discharged from hospital care.
Jane was re-admitted to hospital approximately a month later with bronchiolitis,
which was successfully treated by administering oxygen and Salbutamol. Two
months later she was diagnosed with laryngopharyngeal reflux, which had been
causing issues with feeding on formula. After being prescribed Ranitidine and
changing the formula to a thicker solution, this issue of feeding was resolved.
However, during the same time periods Jane had two apnoeic episodes whilst
travelling in the car, accompanied with stridor. Upon admission to hospital she
3 Mathew M, Saquib S, Rizvi SG. Polyhydramnios: Risk Factors and
Outcome. Saudi Medical Journal2008; 29(2): 256-260.
http://smj.org.sa/index.php/smj/article/view/6141/3915 (accessed 22/02/2015)

was diagnosed with laryngomalacia, however was not of an appropriate age for
the recommended surgical intervention (trimming of the aryepiglottic folds) to be
provided. Her bronchiolitis recurred at 5 months of age as well as 7 months of
age
At 10 months of age, Jane had a respiratory tract infection and was apnoeic when
taking a nap. She was brought in by ambulance to hospital, where there was an
oxygen saturation reading of less than 50%. As such she was commenced on BiPAP and transferred to C-PAP as her saturation improved. Due to this apnoeic
episode as well as a history of snoring when asleep and frequent stridor when
awake, Jane was recommended for a sleep study, which was conducted at the
age of 13 months. This resulted in a diagnosis of Obstructive Sleep Apnoea,
which was managed for the four and a half years subsequent to the diagnosis
with a CPAP machine. Apparently the OSA did resolve at the end of this period of
time however her mother claims that it might have started to recur in the last
month or so, but they have yet to seek medical consultation for it. In addition to
the CPAP machine, the obstructive sleep apnoea was further managed with
adenoidectomy.
In conjunction with the adenoidectomy, Jane had grommets inserted to clear fluid
from her ears. This is due to the unique developments caused by her genetic
disorder which include low set ears, abnormally small sinuses and Eustachian
tubes (which has resulted in hearing impairment and the need for hearing aids
bilaterally). Her smaller ears have also resulted in a greater propensity to be
blocked by wax, which needs to be frequently removed by syringing. Facial
features characteristic of her particular genetic disorder include macrocephaly
and hypoplasia of the mid-face as well as epicanthic folds and malocclusion, the
latter of which required the removal of six of her molar teeth as their
development caused great discomfort. Due to underdeveloped irises, she also
suffers from astigmatism in both eyes and wears glasses to aid her vision.
Following this, Jane underwent MRI imaging, which showed thinning of the corpus
callosum, reduced white matter, enlarged ventricles and delayed myelination.
These findings are consistent with a clinical presentation of developmental delay.
Whilst Jane has consistently been in the 90 th percentile in both weight and
height, she has been delayed in achieving many developmental milestones. She
began to sit at 9 months of age (normal age at which this milestone is achieved
is 5-8 months) to crawl at some time between 12 months and 16 months of age
and walk at 3 years and 3 months of age (normal age at which this milestone is
achieved is usually 12-16 months). Whilst she was babbling at 6 months, she
quietened from the age of 9-12 months, likely secondary to hearing difficulties
arising from the aforementioned underdeveloped Eustachian tubes.
At an older age, which the mother could not recall whilst giving the history, Jane
was diagnosed with hypermobile joints, which in part accounted for her delayed
achievement of the walking development milestone. When aged 5 years, her
paediatrician incidentally noticed that her left tibia was tilted outwards, which
was confirmed by X-ray imaging. An almost vertical left talus was also noted, and
Jane wears orthotics for foot support to ensure she can walk without excess
difficulty.

From generally observing Jane in a school environment, she exhibits echolalia

which in normal development should not persist beyond the age of 2 years and
has severe receptive and expressive language disorder. Similarly, she has not
quite perfected the pincer grip for holding objects and must be reminded and
assisted in holding a pen each time she is given one. Her vocabulary is
somewhat limited to very basic words but her comprehension is quite sound
though simple and heavily dependent on routine tasks, demonstrating significant
difficulty in grasping new concepts. Jane is able to count to 20, albeit with
prompting, and can recite the alphabet, though has difficulty reading and writing
sentences. Based on how she has attained certain developmental milestones,
one can estimate Jane is roughly 4 years old developmentally. This estimation is
reinforced via Janes social interactions, these being limited with her brother
(who is developing at the standard rate and is 7 years old) but which are quite
broad with her classmates who are developmentally also around the same age.
Jane plays happily with several other children in her class, though is quite
irritable when those she is not socially close to come too physically close (yelling
stop! and pushing them away). It is interesting to note that in terms of her
growth, Jane has thrived quite well, being in the 90 th percentile for both her
height and her weight.

Discussion
It is interesting to note that whilst Jane is the only known diagnosed case of a
double duplication in chromosome 5 internationally, that trisomy of chromosome
5 (i.e. a single duplication) is a known rare genetic disorder. Of the documented
cases of trisomy of chromosome 5, they present with much the same features as
Janes double duplication4. These include the facial features that Jane has as well
as the global developmental delay and hypotonia. Depending on Janes health
and how it develops over the next few years, one might be able to draw parallels
between the presentation of both disorders and thus also correlate management,
with treatment and ongoing management of trisomy of chromosome 5 serving as
a precedent for managing double duplication in chromosome 5. There is no
known cure for chromosome 5 trisomy or Janes particular disorder, and as such
management is symptomatic in focus.
Disorders arising from duplications in chromosome 5 often result in a propensity
for poor respiratory function in patients. This is due to the craniofacial syndrome
typical in chromosome 5 duplication disorders (with reduced airway size) as well
as generalised hypotonia, thus leading to a predisposition to obstructive sleep
apnoea. Whilst tonsillectomy and adenoidectomy have been shown to be
effective in potentially opening the airway and improving respiration in adults, in
paediatrics those surgical procedures are often done with curative intent and are
mainline treatment.5 It is interesting to note however, that while studies indicate
that adenotonsillectomy is curative in 73%-95% of paediatric patients (excluding
4 Dobin S. Chromosome 5, Trisomy 5p. National Organisation for Rare Disorders, 2013.
https://www.rarediseases.org/rare-disease-information/rarediseases/byID/990/printFullReportAbuelo DN, Ahsanuddin AN, Mark HFL. Distal 5q
Trisomy resulting from an X;5 translocation detected by chromosome painting. American
Journal of Medical Genetics 1999; 5(94): 392-399.

for obesity), it was not curative in Janes case, which is why she required CPAP
post-operation. Whilst there is evidence CPAP can manage OSA and reduce
complications, there is no evidence that suggests that it is curative in paediatric
patients, which may also explain why Janes OSA might potentially recur.
Physiotherapy has proven to be highly effective in Janes case, as is evident from
her initial hypermobile joints from birth to now being able to walk and play fairly
normally with other children. The literature suggests that physical therapy
focused on strengthening muscles and fitness, correcting and adjusting joint
movement for optimal performance and reducing pain can help patients
overcome difficulties faced by hypermobility. However, despite that evidence
base, there is insufficient data on the clinical outcomes that result from such
interventions and the exact nature of the interventions that will provide the best
outcomes, with the evidence simply pointing towards exercise therapy in general
being of benefit to the patient6.
Speech therapy is considered one of the primary treatments for expressive and
receptive language disorders, however the literature does not provide sufficient
evidence that speech therapy provides any definitive improvement, which is
especially evident in those with receptive language disorders. A 2004 metaanalysis of the literature concluded that speech therapy could potentially be
effective in managing expressive language disorder though, however this is on
the condition that said therapy lasts for longer than 8 weeks at a time 7. As such,
Janes referral to a speech therapist may potentially provide support in managing
her expressive language difficulties, however the literature is inconclusive with
regards to the benefits speech therapy may provide to alleviating receptive
language difficulties.
Perhaps one of the more prominent characteristics of the special needs school
that Jane attended was the emphasis on technology. Although studies provide
mixed results as to how the use of technology in the classroom may enhance
marks, particularly to the HSC level, some of the literature augments the view
that technology, particularly the use of computers, can aid in students with
intellectual disability grasping concepts more effectively 8. This could also be
clearly observed during my time at Janes school, where the iPad was used as a
means to settle numerous students like Jane when they were agitated, and the
use of the smartboard during learning activities was an effective means of
5 Hamilton G, Nixon G, Tai A, Suresh S, Horne R, Rajaratnam S. ADENOTONSILLECTOMY
FOR PAEDIATRIC OBSTRUCTIVE SLEEP APNOEA SUBMISSION FROM THE AUSTRALASIAN
SLEEP ASSOCIATION (ASA). Australian Sleep Association, 2013.

6 Smith TO1, Bacon H, Jerman E, Easton V, Armon K, Poland F, Macgregor AJ.

Physiotherapy and occupational therapy interventions for people with benign joint
hypermobility syndrome: a systematic review of clinical trials.. Disability and
Rehabilitation 2014; 36(10): 797-803.

7 Law J, Garrett Z, Nye C. The Efficacy of Treatment for Children With Developmental
Speech and Language Delay/Disorder. Journal of Speech, Language, and Hearing
Research 2004; 47(4): 924-943.

encouraging participation among students in learning activities, who would

otherwise avoid learning activities in books, worksheets or cards.
There is much debate in educational circles over whether or not special needs
children should be more included in general education environments, the
alternative being they attend a special needs environment for their educational
lives. Studies have shown that students with intellectual disability consistently
have poorer student teacher relationships within the general education
environment, and this lends credence to the view that students like Jane would
benefit more from an environment where their teachers are trained to
specifically mentor students with special needs, which is the case at her school.
One of the main obstacles faced by Jane and her family is the lack of government
financial support for those with rare chromosome disorders. Eligibility for The
Better Start for Children with Disability initiative is limited to a few genetic
disorders that are more common, and as such Janes family does not receive
government support for interventional or ongoing health support services for her
unique genetic disorder9. As such, they cannot afford ongoing physiotherapy or
occupational therapy for Jane who is now limited to receiving speech therapy and
going to a special needs school. This leads to an incomplete management plan
that can affect her ability to develop as she otherwise would.

Conclusion
Due to the low number of cases in rare chromosome disorders, the literature on
targeted therapy for any particular one of them is extremely limited. However,
there is significant evidence to suggest that certain methods of managing the
symptoms and health issues arising from these disorders, as well as providing
providing support with those with intellectual disability and global developmental
delay, can be highly effective. Fortunately, many of the interventions Jane
receives, particularly attending a special needs school with an emphasis on
computer technology to assist in learning, ongoing medical care from allied
health services as well as the hospital care she received to treat her respiratory
issues, have been proven to be beneficial for her ongoing health not only in the
studies that support them but by Jane and her parents own testament. Although
the literature is still inconclusive on the benefit of speech therapy, there is some
evidence that it may still benefit Jane in which case it might still prove to be
useful.
It was an absolute pleasure to become acquainted with Jane and her wonderful
family and a joy to see her enjoy her school environment and continue to thrive
8 Lancioni GE, Van Den Hof E, Furniss F, O'Reilly MF, Cunha B. Evaluation of a computeraided system providing pictorial task instructions and prompts to people with severe
intellectual disability.Journal of Intellectual Disability Research 1999; 43(1): 61-66.

9 Australian Federal Government Department of Health. Disability Better Start for

Children with Disability initiative. http://www.health.gov.au/children-disability (accessed
22/02/2015)

and learn. According to her mother, raising Jane has had many challenges and
obstacles and at times has given rise to difficulties that made it difficult for her
and the family to cope emotionally, however they both love and care for Jane
tremendously and overall it has been an immeasurably valuable experience, a
statement which I can certainly identify with based on my time at Janes school.
Her case might also provide precedent for how rare chromosomal disorders
might be managed in all children who are diagnosed with one.

References
1. Global Genes. R.A.R.E List. http://globalgenes.org/rarelist/ (accessed
22/02/2015).

2. Australian Bureau of Statistics. 2012 Survey of Disability, Ageing and

Carers, 2012.

3. Dobin S. Chromosome 5, Trisomy 5p. National Organisation for Rare

Disorders, 2013. https://www.rarediseases.org/rare-diseaseinformation/rare-diseases/byID/990/printFullReport

4. Abuelo DN, Ahsanuddin AN, Mark HFL. Distal 5q Trisomy resulting from an
X;5 translocation detected by chromosome painting. American Journal of
Medical Genetics 1999; 5(94): 392-399.
5. Law J, Garrett Z, Nye C. The Efficacy of Treatment for Children With
Developmental Speech and Language Delay/Disorder. Journal of Speech,
Language, and Hearing Research 2004; 47(4): 924-943.

6. Smith TO1, Bacon H, Jerman E, Easton V, Armon K, Poland F, Macgregor AJ.

Physiotherapy and occupational therapy interventions for people with
benign joint hypermobility syndrome: a systematic review of clinical
trials.. Disability and Rehabilitation 2014; 36(10): 797-803.

7. Lancioni GE, Van Den Hof E, Furniss F, O'Reilly MF, Cunha B. Evaluation of
a computer-aided system providing pictorial task instructions and prompts
to people with severe intellectual disability.Journal of Intellectual Disability
Research 1999; 43(1): 61-66.

8. Hamilton G, Nixon G, Tai A, Suresh S, Horne R, Rajaratnam

S. ADENOTONSILLECTOMY FOR PAEDIATRIC OBSTRUCTIVE SLEEP APNOEA

 SUBMISSION FROM THE AUSTRALASIAN SLEEP ASSOCIATION (ASA).

Australian Sleep Association, 2013.

9. Australian Federal Government Department of Health. Disability Better

Start for Children with Disability initiative.
http://www.health.gov.au/children-disability (accessed 22/02/2015)
10.Mathew M, Saquib S, Rizvi SG. Polyhydramnios: Risk Factors and
Outcome. Saudi Medical Journal2008; 29(2): 256-260.
http://smj.org.sa/index.php/smj/article/view/6141/3915 (accessed
22/02/2015)