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Down SyndromeA Narrative Review with a

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 Clinical Anatomy 00:0000 (2015)

REVIEW

Down SyndromeA Narrative Review with a

Focus on Anatomical Features
ASHOKAN ARUMUGAM,1* KAVITHA RAJA,2 MAHALAKSHMI VENUGOPALAN,3
BASKARAN CHANDRASEKARAN,4 KESAVA KOVANUR SAMPATH,5
HARIRAJA MUTHUSAMY,1 AND NAGARANI SHANMUGAM6
1
Department of Physical Therapy, College of Applied Medical Sciences,
Majmaah University, Kingdom of Saudi Arabia
2
JSS College of Physiotherapy, Mysore, Karnataka, India
3
PSG College of Physiotherapy, Peelamedu, Coimbatore, Tamil Nadu, India
4
Department of Pulmonary Rehabilitation, PSG Hospitals, Coimbatore, Tamil Nadu, India
5
Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy,
University of Otago, Dunedin, New Zealand
6
RVS College of Physiotherapy, Sulur, Tamil Nadu, India

Down syndrome (DS) is the most common aneuploidy of chromosome 21,

characterized by the presence of an extra copy of that chromosome (trisomy
21). Children with DS present with an abnormal phenotype, which is attributed
to a loss of genetic balance or an excess dose of chromosome 21 genes. In
recent years, advances in prenatal screening and diagnostic tests have aided
in the early diagnosis and appropriate management of fetuses with DS. A myr-
iad of clinical symptoms resulting from cognitive, physical, and physiological
impairments caused by aberrations in various systems of the body occur in
DS. However, despite these impairments, which range from trivial to fatal
manifestations, the survival rate of individuals with DS has increased dramati-
cally from less than 50% during the mid-1990s to 95% in the early 2000s,
with a median life expectancy of 60 years reported recently. The aim of this
narrative review is to review and summarize the etiopathology, prenatal
screening and diagnostic tests, prognosis, clinical manifestations in various
body systems, and comorbidities associated with DS. Clin. Anat. 00:000000,
2015. VC 2015 Wiley Periodicals, Inc.

Key words: Down syndrome; trisomy 21; autosomal aneuploidy; phenotype;

morbidity; mortality

Abbreviations used: ALL, acute lymphoblastic leukemia; AFP, alpha fetoprotein; AML, acute myeloid leukemia; AAI, atlantoax-
ial instability; b-hCG, human chorionic gonadotrophin b-subunit; cf-DNA, cell-free DNA; CI, confidence interval; DS, down
syndrome; FISH, fluorescence in situ hybridization; NT, nucal translucency; PAPP-A, pregnancy-associated plasma protein-A;
TSH, thyroid stimulating hormone; lE3, unconjugated estriol; VSD, ventricular septal defects.

*Correspondence to: Ashokan Arumugam, Department of Physical Therapy, College of Applied Medical Sciences, Majmaah Univer-
sity, P.O. Box 66, Majmaah 11952, Kingdom of Saudi Arabia. E-mail: ashokanpt@gmail.com or a.arumugam@mu.edu.sa
Conict of interest: None declared.
Received 12 November 2015; Accepted 19 November 2015
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ca.22672

C
V 2015 Wiley Periodicals, Inc.
2 Arumugam et al.
INTRODUCTION
In 1866, John Langdon Down rst described the set
of characteristics of a chromosomal disorder that is
now referred to as Down syndrome (DS) (Down,
1866). At that time, Down could only speculate on the
etiology of DS; however, in 1959, Jerome Lejeune dis-
covered that an extra copy of chromosome 21
(Hsa21) caused the condition (Patterson and Costa,
2005).
Down syndrome, or trisomy 21, is the most com-
mon aneuploidy of autosomal chromosomes (Lejeune
et al., 1959). The average, non-gender-specic,
live-birth rate of infants with DS is approximately 1 in
1000 (Fitzgerald et al., 2013). Between 1942 and
1952, the survival rate of children less than 12 months
of age with DS in the United Kingdom was less than
50% (Record and Smith, 1955). A similarly high death
rate (around 40%) among Swedish children with DS
less than one year of age was reported between 1969
and 1973, but by 19992003 this had decreased sig-
nicantly to 4.4% (Englund et al., 2013). As reected
by these data, the life expectancy of this population
has recently increased to approximately 60 years
(Englund et al., 2013). The improved survival rate can
be attributed to factors such as appropriate (early)
management of congenital cardiac malformations and
infectious diseases, along with a healthier diet and bet-
ter health care (Glasson et al., 2014).
Individuals with DS present with a plethora of
comorbidities affecting the respiratory, cardiovascular,
sensory (organs), gastrointestinal, hematological,
immune, endocrine, musculoskeletal, renal and geni-
tourinary, and neurological systems (Scherbenske
et al., 1990; Roizen and Patterson, 2003; Dykens,
2007; Kaski et al., 2010; Bull, 2011; Fitzgerald et al.,
2013; Shiang, 2014). The aim of this article is to
review the etiopathophysiology, prenatal screening,
diagnosis and prognosis of DS, along with the com-
mon structural and functional anomalies of body sys-
tems and associated comorbidities.
ETIOPATHOPHYSIOLOGY
Two hypotheses have been proposed to account for
the role of an additional copy of chromosome 21 in the
characteristics associated with DS. First, the
developmental instability hypothesis evokes a loss of
genetic balance (among the hundreds of genes) in chro-
mosome 21 leading to an imbalance of gene expression
in pathways that control development (Shapiro et al.,
1983; Shapiro, 1997). Second, the gene-dosage effect
hypothesis states that the excess of chromosome 21
genes (three copies instead of the usual two) results in
an abnormal phenotype (Patterson and Costa, 2005;
Hartway, 2009). It has also been proposed that both
these mechanisms could act in conjunction (Patterson
and Costa, 2005; Hartway, 2009).
The various causes of DS include nondisjunction
(95%), translocation (3.2%), and mosaicism (1.8%)
associated with chromosome 21 (Kava et al. 2004).
Nondisjunction occurs because of aberrant cell division
during the formation of ovum or sperm, resulting in
an extra chromosome 21 (24 chromosomes in a
gamete) (NDSS, 2012; Hartway, 2009); thus, after
fertilization, the zygote will have 47 chromosomes
instead of 46. As the word implies, translocation refers
to an additional copy of chromosome 21 that is par-
tially or fully translocated to another chromosome
(Hartway, 2009; NDSS, 2012). In mosaicism, some
but not all cells carry an extra copy of chromosome
21 (Hartway, 2009; NDSS, 2012). Some cases of DS
that result from translocation are associated with a
genetic risk. Nondisjunction and mosaicism mecha-
nisms are not usually inherited, but some families are
more susceptible to inheritance of these aberrations
(NDSS, 2012). The review by Sheets et al. (2011)
gives a detailed summary of the cytogenic ndings,
etiology, and recurrence risk associated with the three
types of mechanisms causing DS.
The reasons for the presence of an excess copy of
chromosome 21 (of maternal [more common] or
paternal origin) remain unclear. Although there is a
greater risk of DS with increasing maternal age (> 35
years), most children with DS are born to mothers
younger than 35 years owing to their higher fertility
rates. Any child can be affected by DS irrespective of
ethnicity, socio-economic status, or country of birth
(Rutter, 2002; NDSS, 2012).
SCREENING AND DIAGNOSTIC TESTS
Prenatal screening, including ultrasound and analy-
sis of maternal serum, is part of routine pregnancy
investigation (Khalil and Pandya, 2006; Sheets et al.,
2011). Non-invasive tests such as the double-marker
test are performed during the rst trimester while the
triple-marker and quadruple-marker (triple marker
test 1 inhibin A) tests are carried out during the sec-
ond trimester to rule out aneuploidies (Cole and
Jones, 2013; Shiefa et al., 2013).
First trimester screening is conducted between 11
and 14 weeks of gestation (Zournatzi et al., 2008).
The tests can include fetal nucal translucency (NT)
and the double-marker test (pregnancy-associated
plasma protein-A [PAPP-A] and free human chorionic
gonadotrophin b-subunit [free b-hCG]). An increased
level of free b-hCG with decreased PAPP-A is sugges-
tive of DS (Wald et al., 1999). Other markers com-
monly observed during the rst trimester with
ultrasound scanning are a short maxilla, absence of a
nasal bone, and abnormal Doppler waveforms in the
ductus venosus (Cicero et al., 2004; Barlow-Stewart
et al., 2007). There is a strong association between
the absence of the nasal bone in the rst trimester
and trisomy 21 as well as other chromosomal abnor-
malities (Cicero et al., 2004). Moreover, cell-free DNA
(cf-DNA) can be identied in the maternal plasma
from 10 weeks of gestation onwards. This test pro-
vides the most effective method of screening for tris-
omy 21 with a reported detection rate of 99%
(Grataco  s and Nicolaides, 2014).
The second trimester screening tests are usually
conducted between 15 and 17 weeks of gestation, up
to 20 weeks. They include ultrasound and triple-
serum (alpha fetoprotein [AFP], unconjugated estriol

[lE3], and free b-hCG) or quadruple-serum (AFP, lE3,
free b-hCG, and inhibin A) marker tests (Barlow-
Stewart et al., 2007). The levels of maternal AFP and
lE3 tend to be reduced in DS, and free b-hCG and
inhibin A seem to be increased (Cicero et al., 2004).
Antenatal ultrasound soft markers indicating DS such
as a thickened nuchal fold, a hypoplastic nasal bone,
short humerus and femur, hydronephrosis, echogenic
intracardia focus, echogenic bowel, single umblical
artery, and (mild) pyelectasis are also screened during
the second trimester (Bethune, 2007).
The diagnostic tests for pregnant women at a high
risk of having a baby with DS include chorionic villus
sampling, done either transabdominally or transvagi-
nally at 1214 weeks, and aminocentesis under ultra-
sound guidance between 15 and 18 weeks of
gestation. Invasive testing has a spontaneous abor-
tion risk of around 1% (Cole and Jones, 2013), so it is
performed only on cases identied by screening as
being at high risk for aneuploidies (Mutton et al.,
1998; Ekelund et al., 2008; Gil et al., 2014).
Karyotyping to detect aneuploidy is possible using
a Giemsa banding technique. Its main drawback is
that it is time consuming (12 weeks). When other
screening tests provide strong evidence of a fetal
anomaly, uorescence in situ hybridization (FISH) can
be performed instead on chorionic villus or amniocent-
esis samples (Stoian et al., 2007) and the results will
be available within one or two days (Cicero et al.,
2004). Karyotyping and FISH can also be carried out
postnatally to conrm the clinical diagnosis of DS
(Sheets et al., 2011).
Compared with the commonly-acknowledged risk
factor of advancing maternal age, screening tests per-
formed with maternal serum markers and ultrasound
are reportedly more effective and efcient in aiding
the clinical diagnosis of DS (Smith-Bindman et al.,
2003).
PROGNOSIS
The most common causes of mortality in DS are
respiratory diseases (pneumonia), congenital heart dis-
eases, circulatory disorders, and dementia (Ster and
Nielsen, 1975; Howells, 1989; Englund et al., 2013).
Children with DS are at increased risk of leukemia and
testicular cancer (Roizen and Patterson, 2003), but
malignancy is not a leading cause of mortality in this
population (Englund et al., 2013). However, mortality is
higher in children with DS than the normal population
(Day et al., 2005). The best predictors of survival in
children with DS are gestational age at delivery, stand-
ardized birth weight, karyotype (trisomy 21/mosaic/
translocation), and the presence of anatomical anoma-
lies (single or multiple) (Rankin et al., 2012).
CLINICAL FEATURES OF DS
Various anomalies of the respiratory, cardiovascu-
lar, sensory (organs), gastrointestinal, hematological,
immune, endocrine, musculoskeletal, renal and geni-
tourinary systems are characteristic of DS. In addi-
Down Syndrome 3
tion, cognitive impairments and psychiatric disorders
have been documented in these children. Morbidity
and mortality rates associated with these clinical man-
ifestations differ slightly among studies. However, the
most common reasons for hospitalization of children
with DS are respiratory disorders (predominantly
because of infection) and congenital heart malforma-
tions (Englund et al., 2013; Fitzgerald et al., 2013).
Respiratory Disorders
Children with DS often present with multiple
respiratory problems due to the inefciency of
mitochondrial protein function in the respiratory epi-
thelium, neuronal regulation, and immune cells with
transcribed human chromosome 21 genes (Pandit and
Fitzgerald, 2012; Watts and Vyas, 2013). Common
respiratory problems include upper respiratory tract
anomalies, recurrent aspiration, obstructive sleep
apnea and recurrent respiratory tract infections (Pan-
dit and Fitzgerald, 2012). Increased oxidative stress
(Pagano and Castello, 2012) and compromised immu-
nity in the body can (Xu et al., 2013) also add to
morbidity.
Obstructive sleep apnea is the most common respi-
ratory disorder, occurring in 3050% of individuals
with DS (Lal et al., 2015). It can be associated with a
narrowed airway, enlarged tonsils and adenoids, mac-
roglossia, mid-face hypoplasia, delayed development
of oromotor function, and micrognathia (Austeng
et al., 2014; Gofnski et al., 2015).
Children with DS can present with obstructive air-
way disease caused by macroglossia, a constricted
nasopharynx, congenital subglottic stenosis, laryngo-
malacia (malacia denotes any abnormal softening of
the tissues), tracheobronchomalacia, and tracheal ste-
nosis (Jacobs et al., 1996; Pravit, 2014). Although
appropriate surgical intervention can decrease airway
obstruction, residual obstruction remains common in
this population (Jacobs et al., 1996). In addition to
these factors, poor oromotor coordination (dystonia of
oral muscles) and a reduced gastroesophageal reex
can predispose to recurrent aspiration (Abadie and
Couly, 2012).
Patients with DS have increased levels of inamma-
tory markers such as interleukins (IL-1b, IL-10, and
IL7), tumor necrosis factor, and cytokines, and
decreased levels of immunoglobulins (Pagano and
Castello, 2012). There is also a signicant increase in
lipid peroxidation, oxidative DNA damage, and plasma
levels of uric acid, allantoin, and a decrease in
hypoxanthine and xanthine in this population. This is
partially explained by the down-regulation of mito-
chondrial components and oxidative stress (Pagano
and Castello, 2012).
Low mitochondrial activity in airway lymphocytes
and macrophages can cause a reduced immunological
response in DS (Xu et al., 2013). Infections of the
upper (e.g. sinusitis, rhinitis, middle ear infections,
tonsillitis) and lower (pneumonia and bronchiolitis)
respiratory tract are highly prevalent in children with
the condition (Bloemers et al., 2010). Respiratory syn-
cytial virus is the most common cause of lower
4 Arumugam et al.
respiratory tract infection in these children (Bloemers
et al., 2007, 2010). Poor oral hygiene, innate apopto-
sis of granulocytes, decreased immune status, and
recurrent aspiration can lead to recurrent sepsis and
community-acquired pneumonia (Xu et al., 2013).
Cardiovascular Disorders
A recent study in the United Kingdom documented
a 42% incidence of cardiovascular abnormalities in a
DS population (Irving and Chaudhari, 2012), while the
prevalence of congenital cardiac diseases ranged
between 40% and 76% depending on the cohort stud-
ied (Paladini et al., 2000).
Ferencz et al. (1989) proposed that genetic errors
of endothelial cells may constitute an initiating sus-
ceptibility to cardiac maldevelopment with possible
variability in expression. Moreover, an extra copy of
chromosome 21 can lead to at least a 50% increase
in RNA in fetal cardiac mitochondria (increased tran-
scription of Hsa21 genes) and extracellular matrices,
contributing to congenital cardiac defects (Conti et al.,
2007). Downregulation of mitochondrial proteins in
the hearts of children with DS has also been pro-
posed, especially oxidative phosphorylation enzymes,
along with upregulation of extracellular matrix genes
(Conti et al., 2007). To be specic, it has been claimed
that reduced mitochondrial membrane potential is piv-
otal in mitochondrial downregulation and impairment
of oxidative phosphorylation pathways (Conti et al.,
2007). In general, it has been assumed that impaired
redox and oxidative phosphorylation pathways in
heart mitochondria are the main reasons why congen-
ital cardiac defects develop in children with DS.
In contrast, some researchers have claimed that
the mere presence of an extra copy of chromosome
21 cannot be the sole cause of cardiac anomalies
because not all children with DS are born with such
anomalies (Li et al., 2012). Using mouse models, Li
et al. (2012) demonstrated the additive effects of
genetic modiers (mutant CRELD1 and HEY2 genes
sequenced from humans with DS) in causing congeni-
tal heart defects.
The chromosome 21 aneuploidy can result in endo-
cardial cushion defects (complete or incomplete) (Fer-
encz et al., 1989). The congenital cardiac disorders
most commonly associated with DS are atrioventricu-
lar defects (45%) and ventricular septal defects (VSD)
(35%), while abnormalities such as isolated secun-
dum atrial septal defects (8%), isolated tetrology of
Fallot (4%) and isolated patent ductus arteriosus are
less frequent (Freeman et al., 1998). The major com-
plication of cardiac anomalies in DS is pulmonary
artery hypertension, which can progress to cardio-
genic shock and eventually death (de Rubens Figueroa
et al., 2003).
It is said that the incidence of VSD is low because
VSD close spontaneously as a result of adequate
available oxygen during early intrauterine life. In high
altitude countries where oxygen availability is low,
there is sometimes a high incidence of VSD owing to
delayed closure (de Rubens Figueroa et al., 2003).
The advent of investigations such as serum marker
tests, amniocentesis, fetal echocardiography, DNA
microarray technology, and functional analysis of fetal
hearts has made early detection of congenital cardiac
defects in fetuses with DS possible. Moreover, most of
the anomalies in infants with DS are reportedly suita-
ble for complete surgical correction with single ventri-
cle palliation recommended for children with complex
cardiac anomalies (Irving and Chaudhari, 2012). Car-
diac transplantation with successful outcome has also
been reported for two children (one with cardiomay-
opathy and the other with end-stage cardiac failure)
presenting with DS (Irving and Chaudhari, 2012). In
19962006, the one year survival rate for children
diagnosed with cardiac dysfunction was 94% owing to
a reduction in post-operative complications (Irving
and Chaudhari, 2012). An 8.5 year retrospective
observational cohort study highlighted inconsistent
preventive healthcare for adults with DS, and the
authors recommended that appropriate screening and
early identication of comorbidities associated with
DS and adherence to preventive healthcare recom-
mendations would improve clinical outcomes in this
population (Jensen et al., 2013).
Craniofacial Dysmorphia
Children with DS are predominantly brachycephalic
(62.3%), but they can also be hyperbrachycephalic
(27.3%), dolicocephalic (7.8%), or mesocephalic
(2.6%). In a retrospective analysis of 524 individuals
with DS, more than 50% were found to have craniofacial
defects such as a downward slant of the eye lids medially
(83.9%), ear anomalies (66.9%), palpebronasal (epi-
canthal) folds (56.9%), and a at face (50.9%) (Kava
et al. 2004). In addition, hypertelorism (increased inter-
ocular distance) and a at nasal bridge appear to be pre-
dominant in this population (Rahul et al., 2015).
Ear and Hearing Disorders
Ear problems such as inner ear dysplasia/hypopla-
sia, vestibular malformations, lateral semicircular
anomalies, and conductive, mixed or neurosensory
hearing loss are common in patients with DS (Blaser
et al., 2006). Moreover, a high prevalence of chronic
otitis media with effusion ( 60%) has also been
reported (Maris et al., 2014), with hearing loss recov-
ered via insertion of grommets (tympanostomy tubes)
(Paulson et al., 2014).
Oral Disorders
In general, the oral dysmorphic features common
among people with DS are a ssured tongue and a
high arched palate (Shukla et al., 2014; Rahul et al.,
2015). In addition to these two traits (each with a
prevalence of 79%), a recent epidemiological survey
of children with DS (n 5 70) in India noted other oral
manifestations such as macroglossia (83%), marginal
gingivitis (93%), microdontia (63%), hypodontia
(41%), an anterior open bite (23%) and periodontitis
(11.5%) (Rahul et al., 2015). Some of these ndings

are consistent with other reports (Brown and Cunning-
ham, 1961; Cohen and Winer, 1965; Undeutsch et al.,
1970; Gullikson, 1972; Kava et al., 2004). In addition,
other aberrant oral conditions such as malocclusion
(between 3% and 55%), congenital absence of teeth
(34%), delayed teeth eruption (10%), angular cheili-
tis (22%), and ankyloglossia (13%) have also been
reported in children with DS (Shukla et al., 2014).
Eye and Vision Disorders
Vision problems evident in DS include severe
refractive errors (50%) and cataracts (15%) (Bull,
2011). In addition, strabismus (47%), nasolacrimal
duct obstruction (36%), and nystagmus (16%) have
been reported (Stephen et al., 2007). Other ophthal-
mic conditions such as retinal hemorrhage and macu-
lar hypoplasia are rare among affected children
(Stephen et al., 2007). For children with DS, standard
ophthalmological examination around three years of
age includes ophthalmoscopy, cycloplegic refraction,
and orthoptic assessment with subsequent follow-up if
required. These assessments are best performed in a
quiet environment with no distraction using appropri-
ate procedures (Stephen et al., 2007).
Gastrointestinal Tract Disorders
Gastrointestinal defects such as duodenal stenosis/
atresia (3.9%), anal stenosis/atresia (1.0%), Hirsch-
sprung disease (0.8%), esophageal atresia with or
without tracheoesophageal stula (0.4%), and pyloric
stenosis (0.3%) (Freeman et al., 2009) have been
reported (overall frequency 7%). In 2011, Bull docu-
mented that these malformations could affect up to
12% of children with DS. Interestingly, Freeman et al.
(2009) reported no association between gastrointesti-
nal anomalies and an extra chromosome (21), mater-
nal age, or infant sex or age among the children
enrolled in the Atlanta/National Down Syndrome
Projects.
The prevalence of celiac disease in DS is about 5%
in Italian patients, manifesting in classical form with
diarrhea and vomiting (65%), a silent form (20%), or
with atypical symptoms such as short stature/anemia
(11%) (Bonamico et al., 2001). The etiology of the
high prevalence of celiac disease in DS remains uncer-
tain (Zachor et al., 2000). On the basis of previous
studies (Iacono et al., 1990; Castro et al., 1993;
Zubillaga et al., 1993), Zachor et al. (2000) claimed
that the expression of histocompatibility antigens of
genetic origin (HLA-DR-3) in DS might cause celiac
disease, but no association between the type of DS
and celiac disease has been advocated. Moreover, no
association between celiac disease and maternal age/
infant sex/diabetes mellitus (type I) in DS has been
documented (Ma rild et al., 2013). In DS, the screen-
ing of celiac disease relies on the identication of
associated serum antibodies (e.g., immunoglobulin
[Ig]A-antiendomysium antibodies) and intestinal
biopsy to conrm villous atrophy (Zachor et al., 2000;
Bonamico et al., 2001; Ma rild et al., 2013). System-
atic screening to ensure early diagnosis of celiac dis-
Down Syndrome 5
ease has been recommended for patients with DS as
their risks for autoimmune diseases, anemia, and fail-
ure to thrive are greater than normal (Bonamico
et al., 2001).
Hematological Abnormalities and
Immunodeciency
Abnormalities of the immune system have been
associated with DS (Kusters et al., 2009). Moreover,
increased incidences of leukemia, hypothyroidism,
malnutrition (zinc deciency), celiac disease and dia-
betes mellitus in children with DS aggravate their
immune deciency (Ram and Chinen, 2011). Leuke-
mia, for example, is estimated to be 15 to 20 times
more frequent in children with DS (Whitlock, 2006).
Evidence indicates that DS itself is an independent
risk factor for the development of both acute lympho-
blastic leukemia (ALL) and acute myeloid leukemia
(AML) (Lange, 2000); the presence of an additional
chromosome being identied as the underlying basis
for the increased risk of ALL (Berger, 1997). ALL in DS
is characterized by unique clinical features that include
heightened sensitivity to methotrexate and an
increased propensity to infections (Whitlock, 2006);
however, overall survival for ALL is better in children
with DS than in children without DS (Gamis, 2005).
Other autoimmune conditions also have a higher
incidence among individuals with DS than in the gen-
eral population. For example, diabetes mellitus (rate
ratio 2.8; 1.0 to 6.1, 95% condence interval [CI])
and celiac disease (rate ratio 4.6; 1.3 to 12.2, 95%
CI) are more common in DS cohorts than controls
(Goldacre et al., 2004). Along with leukemia, respira-
tory infections such as pneumonia remain major
causes of morbidity and mortality in DS (Yang et al.,
2002). A hypothesis proposed to explain the higher
rates of infections and autoimmune diseases is abnor-
mally precocious aging (Cossarizza et al., 1990,
1991). The higher percentage of natural killer cells
found in DS is consistent with this hypothesis (Cossar-
izza et al., 1991). Further, impairments of B-cell, T-
cell, and phagocytic cell functions have also been
noted in DS (Kusters et al., 2009). Altogether, the
underlying immune deciency enhances the increased
risk of infection, especially during periods of immune
compromise, which occur in ALL and during its treat-
ment. Although intensication of therapy may not be
feasible in this population, non-cytotoxic agents such
as monoclonal antibodies have been recommended
for managing ALL in DS (Kusters et al., 2009).
Endocrine Disorders
Thyroid dysfunction is the most common endocrine
abnormality in patients with DS (Hawli et al., 2009;
Iughetti et al., 2014), but prevalence estimates vary
widely, ranging between 3% and 54% in adults (Hawli
et al., 2009). The established risk factors for thyroid
dysfunction in DS include old age and female sex
(Rose and Brown, 2006). A spectrum of thyroid disor-
ders have been reported in DS including congenital,
primary or subclinical hypothyroidism, autoimmune
6 Arumugam et al.
thyroiditis, and hyperthyroidism (Tu ysu
z and Beker,
2001; Purdy et al., 2014).
Evidence indicates that the frequency of hypothyr-
oidism in neonates with DS is 28 times higher than
expected in the general population (Purdy et al.,
2014). Recently, a 10-year longitudinal study demon-
strated that the probability of acquired thyroid dys-
function in DS increased from 30% at birth to 49% at
10 years of age (Iughetti et al., 2014). Several mech-
anisms have been proposed to explain the increased
incidence of hypothyroidism in DS, including immatur-
ity of the hypothalamic-pituitary-thyroid axis (Sharav
et al., 1991), inappropriate thyroid stimulating hor-
mone (TSH) secretion (Grun ~ eiro de Papendieck et al.
2002), TSH insensitivity (Gibson et al., 2005), and
reduced TSH bioactivity (Gibson et al., 2005). Thyroid
hormone replacement in children with DS can improve
hypothyroidism or subclinical hypothyroidism (Hawli
et al., 2009; Purdy et al., 2014).
Musculoskeletal Anomalies
Abnormalities of the musculoskeletal system have
frequently been reported in the literature and mostly
relate to ligament laxity, a distinctive feature of DS. In
the cervical spine region, ligament laxity can give rise
to occipitocervical instability and atlantoaxial instabil-
ity (AAI). Proposed causes for occipitocervical instabil-
ity in DS include retropharyngeal ligament laxity and/
or bony anomalies of the upper cervical spine with or
without aberrant muscle tone (Hankinson and Ander-
son, 2010). Patients with DS have less complete
development of the occipital condyles than healthy
children (Browd et al., 2008). This could predispose to
atlantooccipital instability owing to lack of bony con-
gruence of the joint.
About 1035% of patients with DS are affected by
AAI (Alvarez and Rubin, 1986; Roy et al., 1990;
Cremers et al., 1993) but only 12% present with cer-
vical myelopathy (Pueschel et al., 1984; Pueschel
et al., 1987; Hankinson and Anderson, 2010). In addi-
tion, os odontoideum (separation of a portion of the
dens from the body of the axis [C2]) (Semine et al.,
1978), hypoplasia of the atlas (Taggard et al., 2000;
Matsunaga et al., 2007), bid atlantal arches
(Menezes, 2008) or ossiculum terminale (congenital
non-union of the dens from a terminal ossicle located
above the transverse ligament) (Ali et al., 2006) can
coexist in DS. On the other hand, an intrinsic collagen
decit could cause transverse ligament laxity (Pue-
schel and Scola, 1987). As a result, the odontoid pro-
cess cannot be stabilized against the anterior arch of
the atlas, leading to AAI with a reduction in vertebral
canal size, which could cause compression of the spi-
nal cord during cervical spine movements in the sagit-
tal plane (Hankinson and Anderson, 2010). AAI can
be managed surgically by posterior occipitoaxial stabi-
lization using C2 laminar screws (Kuroki et al., 2012)
while atlantooccipital and atlantoaxial subluxation is
treated by internal xation and fusion of the occiput to
C3 (Johnson et al., 2013). Surgical stabilization of
upper cervical instability followed by appropriate reha-
bilitation can relieve spinal cord compression and
resolve neurological symptoms (Kuroki et al., 2012).
However, the chances of post-operative complications
following occipito-cervical stabilization range from
73% to 100% (Segal et al., 1991; Doyle et al., 1996).
Sankar and colleagues (2011) cited studies of the
prevalence of instability of the hip (1.25% to 7%) in
individuals with DS. Specically, the prevalence of
acetabular dysplasia in DS is around 9% (Hresko
et al., 1993) and this condition can lead to pain, dif-
culty in gait, and subluxation of the hip joint. Acetabu-
lar retroversion has been reported to be the most
common cause of posterior subluxation/
dislocation of the hip in patients with DS (Sankar
et al., 2011, 2012). Complete redirectional acetabular
osteotomy is a promising surgical intervention for cor-
recting acetabular retroversion and restoring hip sta-
bility in these individuals (Sankar et al., 2011). Other
treatment options to manage hip instability such as
capsular plication, innominate and femoral (derota-
tion) osteotomies, and total hip arthroplasty (Bennet
et al., 1982) have been reported, but there is no clear
consensus about the best treatment option for man-
aging hip instability in this population.
Other musculoskeletal abnormalities include dislo-
cation/subluxation of the patella, deformities such as
genu valgum, pes planus, metatarsus primus varus,
and scoliosis (Diamond et al., 1981; Yam et al.,
2008), all of which have been attributed to ligament
laxity (Galli et al., 2014). In addition, brachycephaly,
brachydactyly, wide hands, fth nger clinodactyly,
increased web space between the great and second
toes, and short stature have been documented as
possible morphological changes (Roizen and Patter-
son, 2003).
No articles could be found describing variations in
muscle and ligament morphology in DS. Some proposals
explain the reduced motor skills as resulting from physi-
ological alterations or adaptations in DS (Malak et al.,
2015). However, no empirical data are available.
Renal and Genito-Urinary Tract Disorders
On the basis of a retrospective cohort study, Kupfer-
man et al. (2009) reported a prevalence of 3.2% for
renal and urinary tract malformations in DS. They
reported a high risk of cystic dysplastic kidney, renal
agenesis, hydronephrosis, anterior urethral obstruc-
tion, and anterior urethral obstruction in this popula-
tion. However, the risk of an ectopic kidney (OR: 1.6
[95% CI: 0.211.2]) or ureteropelvic junction obstruc-
tion is reportedly low in DS (Kupferman et al., 2009).
Other urogenital anomalies such as cryptorchidism
(undescended or maldescended testes), bladder exs-
trophy, posterior urethral valves, hypospadias (urethral
opening on the inferior aspect of the penis), testicular
microlithiasis, testicular malignancy, and infertility
have also been noted in DS (Mercer et al., 2004;
Vachon et al., 2006; Ebert et al., 2008). Patients with
DS can present with either neurogenic or non-
neurogenic bladder dysfunctions (Ebert et al., 2008). A
review of the literature by Mercer et al. (2004)
reported renal hypoplasia, glomerular microcysts, and

obstructive uropathy as the most common urological
abnormalities in DS.
In addition to clinical examination, anomalies of the
renal and genitourinary tract in DS must be identied
early using clinical examination, ultrasound, urody-
namic assessment, and other relevant investigations
to diagnose the problem and decide on appropriate
conservative or surgical measures (Kupferman et al.,
2009; Mercer et al., 2004).
Psychiatric Disorders
The prevalence of psychiatric disorders in DS
ranges between 22.1% and 38% (Dykens et al.,
2015). Some risk factors associated with psychiatric
disorders in DS are age, gender, serotonin (5-
hydroxytryptamine) dysfunction, sleep problems, life
stressors, hypothyroidism, cardiac surgery, obesity,
mosaicism, family genetics, personality, and strength
(Dykens, 2007). Mental health disorders in DS mani-
fest in different age groups (Dykens, 2007). Young
children with DS appear to have lower overall rates of
disruptive behavior and distinctive social, motivational
and attention proles. Children with DS have a lower
risk of developing signicant psychopathology than
other groups of children with intellectual disabilities
such as fragile X syndrome or cerebral palsy. Recently,
high rates of psychosis and depression have been
reported among young adults and adolescents with
DS (Collacott et al., 1992; Zigman, 2013; Dykens
et al., 2015). Other psychopathologies noted in adults
with DS include phobias, obsessive-compulsive disor-
ders, anorexia nervosa and other eating disorders,
Tourette syndrome, and paraphilias (aberrant sexual
desires) (Dykens et al., 2015). The link between Alz-
heimers disease and adults with DS has been well
documented (Zigman, 2013). Some risk factors pre-
disposing to Alzheimers disease in DS include prema-
ture aging with early deposition of amyloid beta
protein and neurobrillary tangles in the cerebral cor-
tex, oxidative injury causing neurodegeneration, a
greater predisposition to decreased estrogen levels
(post-menopause) in women, and metabolic syn-
drome predominantly associated with high adiposity
(Head et al., 2012; Zigman, 2013). Considering the
broad range of psychopathologies across different age
groups in individuals with DS, a combination of treat-
ment approaches to ameliorate distressful symptoms
has been advocated. These include cognitive-
behavioral therapy, psychotherapy, and promoting
positive states (Dykens, 2007).
CONCLUSION
DS resulting from trisomy 21 caused by nondis-
junction, translocation, or mosaicism can lead to a
myriad of symptoms related to physical, physiological,
and psychological impairments associated with vari-
ous systems of the body. Despite the many comorbid-
ities that coexist in individuals with DS, survival rates
have changed dramatically from less than 50% in
the 1940s (Record and Smith, 1955) to 4.4% at
the turn of the century (Englund et al., 2013) for chil-
Down Syndrome 7
dren under one year of age. This is coupled with
increased longevity, with adults now living to around
60 years of age because of advances in prenatal
screening and diagnosis, appropriate early medical
intervention/care (conservative and/or surgical), and
changes in the attitude of the community toward nor-
malization of the lives of individuals with DS (Englund
et al., 2013).
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