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Received: 16 October 2019    Revised: 19 December 2019    Accepted: 2 January 2020

DOI: 10.1111/apa.15153

REVIEW ARTICLE

Multiorgan involvement and management in children with

Down syndrome

Niamh Lagan1,2  | Dean Huggard1 | Fiona Mc Grane1,2 | Timothy Ronan Leahy3 |

Orla Franklin4 | Edna Roche1,5 | David Webb1,6 | Aengus O’ Marcaigh7 | Des Cox8 |
Afif El-Khuffash9 | Peter Greally1,10 | Joanne Balfe1,2 | Eleanor J. Molloy1,2,11

1
Paediatrics, Academic Centre, Tallaght
Hospital, Trinity College, The University of Abstract
Dublin, Ireland Aim: To review multiorgan involvement and management in children with Down syn-
2
Department of Neurodisability and
drome (DS).
Developmental Paediatrics, Children’s
Health Ireland at Tallaght, Dublin, Ireland Methods: A literature review of articles from 1980 to 2019 using the MEDLINE in-
3
Immunology, Our Lady’s Children’s Hospital terface of PubMed was performed using the following search terms- [Down syn-
Crumlin, Dublin, Ireland
4
drome] or [Trisomy 21] AND [Cardiology] or [Respiratory] or [neurodevelopment] or
Cardiology, Children’s Health Ireland at
Crumlin, Dublin, Ireland [epilepsy] or [musculoskeletal] or [immune system] or [haematological] or [endocrine]
5
Paediatric Endocrinology, Tallaght or [gastrointestinal] or [ophthalmological] or [Ear Nose Throat] or [dermatology] or
University Hospital Dublin, Ireland
6
[renal].
Department of Neurology, Children’s
Health Ireland at Crumlin, Dublin, Ireland Results: Congenital heart disease particularly septal defects occur in over 60% of
7
Department of Haematology & Oncology, infants with DS and 5%-34% of infants develop persistent pulmonary hypertension of
Children’s Health Ireland at Crumlin, Dublin,
the newborn irrespective of a diagnosis of congenital heart disease. Early recognition
Ireland
8
Department of Respiratory, Children’s
and management of aspiration, obstructive sleep apnoea and recurrent lower res-
Health Ireland at Crumlin, Dublin, Ireland piratory tract infections (LRTI) could reduce risk of developing pulmonary hyperten-
9
Department of Neonatology, Rotunda sion in later childhood. Children with DS have an increased risk of autistic spectrum
Hospital, Dublin, Ireland
10 disorder, attention deficit disorder and epilepsy particularly infantile spasms, which
Department of Paediatric Respiratory
Medicine, Children’s Health Ireland at are associated with poor neurodevelopmental outcomes. Congenital anomalies of the
Tallaght, Dublin, Ireland
11
gastrointestinal and renal system as well as autoimmune diseases, coeliac disease,
Neonatology, CHI at Crumlin, Dublin,
Ireland arthropathy, thyroid dysfunction fold diabetes mellitus and dermatological conditions
are more common. Hearing and visual anomalies are also well recognised association
Correspondence
Niamh Lagan and Eleanor Molloy, with DS (Table 1).
Department of Paediatrics, Trinity Centre Conclusion: Children with DS are at an increased risk of multiorgan comorbidities.
for Health Sciences, Tallaght University
Hospital, Dublin 24, Ireland. Organ-specific health surveillance may provide holistic care for the children and fami-
Emails: lagann@tcd.ie (NL); Eleanor.molloy@ lies with DS throughout childhood.
tcd.ie (EM)

Funding information
National Children's Hospital Fund, Tallaght

Abbreviations: AAI, Atlanto-axial instability; AAP, American Association of Paediatrics; A-DS, Arthropathy of Down Syndrome; ALL, Acute Lymphoblastic Leukaemia; AML, Acute
Myeloid Leukaemia; ASD, Atrial Septal Defect; AVSD, Atrioventricular septal Defect; BMI, Body Mass Index; BMI, Body Mass Index; CAKUT, congenital anomalies of the kidney and
urinary tract; CHD, Congenital Heart disease; CVID, Common Variable Immunodeficiency; DA, Duodenal atresia; DSMIG, Down Syndrome Medical Interest Group; ECG,
Electrocardiogram; EEG, Electroencephalogram; ENT, Ear, Nose and Throat; GI, Gastrointestinal; HLA, Human Leukocyte Antigen; ID, Intellectual disability; IgA, Immunoglobulin A; IS,
Infantile spasms; LRTI, Lower Respiratory Tract Infections; MCV, Mean Red Cell Volume; ML-DS, Myeloid Leukaemia of DS; OAHI, obstructive apnoea hypopnoea index; OIDSC, Oxford
Imperial Down Syndrome Cohort; OME, Otitis media with effusion; PFA, Plain Film Radiograph; PGALS, Paediatric Gait, Arms, Legs and Spinal; PH, Pulmonary Hypertension; PPHN,
Persistent Pulmonary Hypertension of the Newborn; PSG, Polysomnography; SDB, Sleep Disordered Breathing; SNHL, Sensorineural Hearing Loss; T1D, Type 1 Diabetes; TAM,
Transient Abnormal Myelopoiesis; TFT, Thyroid Function Testing; TPO AB, Thyroid Peroxidase antibodies; tTG, tissue transglutaminase; VSD, Ventricular Septal Defect.

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1096     © 2020 Foundation Acta Pædiatrica. wileyonlinelibrary.com/journal/apa Acta Paediatrica. 2020;109:1096–1111.
Published by John Wiley & Sons Ltd
LAGAN et al.
University Hospital, Dublin & National
KEYWORDS
Children's Research Centre, Crumlin,
Dublin, Ireland. down syndrome, health surveillance guidelines, multiorgan Involvement, screening, Trisomy
21
1 |  I NTRO D U C TI O N
Down syndrome (DS) or Trisomy 21 is the most common chromo-
somal abnormality accounting for 8% of all registered cases. The in-
cidence of Down syndrome is every 1 in 700 live births in the United
States, with an overall prevalence of 10 per 10 000 births in Europe.
DS is caused by the presence of all, or part of a third copy of chromo-
some 21. This extra genetic material is responsible for the classical
facial characteristics, multiple malformations, intellectual disability,
immune and endocrine dysfunction associated with DS.
Although DS has a variable phenotype there are many com-
mon physical manifestations such as hypotonia, epicanthic folds,
flat nasal bridge, single palmar crease and sandal toe gap.1 Children
with DS have an increased risk of congenital anomalies includ-
1,2
ing congenital heart defects and abdominal wall abnormalities.
Secondary to the differences in their anatomy and hypotonia chil-
dren with DS are at increased risk of hearing loss, ophthalmological
problems, obstructive sleep apnoea as well as hip dysplasia and pes
planus.3 In addition, DS is the most common recognisable genetic
syndrome associated with abnormal immune function and immune
defects. Individuals with DS have a higher incidence of autoimmune
disorders.4 The increased susceptibility to infections has been as-
sociated with atypical immune function in conjunction with various
non-immune related medical and anatomical comorbidities. 2,5 The
prevalence of leukaemia is estimated to be up to 15-20 times more
frequent in children with DS and although leukaemia treatment is
6,7
improving, it is still a major cause of mortality in children with DS.
The life expectancy of people with Down syndrome increased
dramatically between 1960 and 2007, from 10 to 47  years old.
Recent decades have seen a substantial increase in the life expec-
tancy of children with DS, this has been primarily associated with
advances in successful early treatment of CHD.1,9 Presence of a
heart defect increases the risk of death in the infant period by nearly
fivefold and continues to be one of the most significant predictors
of  mortality  until the age of 20  years.10 The implementation of
medical guidelines with preventative health care programmes will
1
continue to help improve life expectancy and quality of life. Young
people and adults with DS are at markedly increased risk of early-on-
set Alzheimer's disease and by 55-60 years of age 40% will develop
dementia.11 After age 35, mortality rates double every 6.4 years in
11,12
DS as compared to every 9.6 years for people without DS. The
implementation of medical guidelines with preventative health care
programmes screening for associated multiorgan involvement con-
tinues to help improve life expectancy and quality of life.1 Paediatric
healthcare guidelines have been well established internationally via
the Down Syndrome Medical Interest Group (DSMIG) and American
Association of Paediatrics (AAP), and there is now a growing move-
ment for the development for same for the adult population.13,14
|
      1097
Key notes
• Down syndrome (DS) is associated with over 80 con-
ditions such as congenital anomalies, sleep disordered
1 breathing, autoimmune conditions and neurodevelop-
mental disorders.
• Individuals with DS have an increased risk of respira-
tory infections, with 30% higher risk of mortality with
sepsis secondary to anatomical differences and immune
dysfunction.
• Comprehensive management guidelines should be de-
veloped to ensure standardised holistic care for the chil-
dren and families with DS.
2 | C A R D I AC I N VO LV E M E NT
Congenital heart disease (CHD) is frequently diagnosed in infants
born with DS. It has significant impact on morbidity and mortality.
In infants born with DS, 54%-66% will have a diagnosis of CHD.15-17
Recommendations from the AAP and DSMIG UK and Ireland include
cardiology review and echocardiogram in the first 6  weeks of life,
however, in most tertiary level centres, this occurs within the first
few days of life.13,14 Timely surgical correction is necessary to pre-
vent the development of Eisenmenger syndrome and pulmonary hy-
pertension. There has been a significant shift in the attitude towards
8
the treatment of children with DS and together with the improve-
ments in early initiation with corrective surgery the life expectancy
of children with DS has dramatically increased from 12 years in 1940
to over 60 years of age today.9,15 Recent studies have shown a de-
cline in the incidence of CHD over time, which have been suggested
to be related to increased prenatal detection of CHD with a resultant
increased number of selective terminations.15,16,18
In unselected populations, septal defects are most commonly as-
sociated with DS, particularly atrioventricular septal defects (AVSD),
followed by ventricular septal defects (VSD), and atrial septal defect
(ASD). In a recent population-based cohort study of infants born
with DS and CHD, AVSD was diagnosed in 42%, VSD in 22% and
ASD in 16%.16 In countries were termination occurs, a shift in the
incidence of complex CHD has been recently noted, with AVSD and
VSD occurring in similar frequency, 30% and 31%, respectively.16
Martin et al reported 66% (n = 80/121) of live birth infants born with
DS had CHD in a region were prenatal screening is not routinely of-
fered and termination is restricted.17
Patent ductus arteriosus and tetralogy of Fallot are associ-
ated with children with DS. The rate of conotruncal defects is only
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1098       LAGAN et al.

TA B L E 1   Review of multiorgan involvement in children with Down syndrome

Organ Issues Management

16
Cardiac • Septal defect • Cardiovascular examination within 24 hours of birth including
Involvement a. AVSD-42% pulse oximetry
b. VSD-22% • ECG for superior axis
c. ASD-16% • Cardiology review with echo as soon as possible, no later
• Pulmonary hypertension than 6 weeks of age, even if foetal echo performed.
a. PPHN • If corrective cardiac surgery long term cardiology follow-up
▪. 5%-34% of DS population, no difference between needed
infants with and without CHD9,17 • Early recognition and management of aspiration, obstructive
b. PH in childhood sleep apnoea and recurrent LRTI could reduce risk of
▪. Associated with CHD in 44.8% and respiratory developing PH in later childhood
causes in 17.9%23 • Regular cardiovascular assessment for young people and
adults to exclude valvular dysfunction
Neurological Issues • Epilepsy • Low threshold for referral for EEG if any unusual flexor
1. Infantile spasms 2%-13%38 movements to assess for hypsarrhythmia
▪. Lower risk of developing subsequent epilepsy40 • Evidence of repetitive play, limited social communication
▪. Associated with poor neurodevelopmental and other behaviours should prompt interprofessional
outcomes.36 assessment for presence of a comorbid neuropsychiatric
2. Increased risk of other seizure types disorder
3. Association with autistic spectrum disorder (10%-
18%) and attention deficit hyperactivity disorder28
Gastrointestinal • Structural issues- • Comprehensive new-born examination and history
Issues 1. Congenital anomalies • The following should prompt urgent assessment:
▪. Duodenal atresia ( 3%-13%) 45 a. Meconium < 48 hours
▪. Anal Stenosis/ atresia (1%-4%) 47 b. Bilious vomiting
▪. Oesophageal atresia/ Tracheoesophageal atresia c. Increased secretions
(0.3%-0.8%) 47 d. With abdominal distension
▪. Hirschsprung's Disease (1%-3%) 48 • Consider PFA, contrast study, surgical review and possible
• Functional biopsy
1. Constipation • Constipation is prominent issue:
2. Gastro-oesophageal reflux a. Initially should be combatted with dietary changes
3. Coeliac Disease-(5%-7.5%)52,53 b. Addition of medication-macrogols or lactulose if necessary
c. If refractory consider late diagnosis of Hirschsprung's
Disease
• GOR occurs frequently in infants < 12 months;
a. Advise on feeding position and pacing.
b. Medication such as H2 blocker or proton pump inhibitor
may be required
• Coeliac disease may have insidious presentation (abdominal
pain, constipation, behavioural changes, weight loss)
a. Low threshold for investigation with IgA and TTG.
b. Establishing HDL status and elimination of those who do
not carry HLA-DQ2 /8 will reduce the numbers needed to
screen by 60%
Endocrine & • Hypothyroidism • Routine newborn screening will detect congenital
Growth a. Congenital thyroid disease hypothyroidism.
▪. 26-fold increase compared with general • DSMIG UK and Ireland recommend annual TFT & TPO Ab
population55,139 antibody levels until age 5 years and at least biannually
b. Autoimmune hypothyroidism thereafter13
▪. Associated with TPO Ab • AAP recommend annual TFTs14
c. Subclinical hypothyroidism (25%-60%)57,139 • If symptoms of polydipsia, polyurea and weight loss perform
▪. Tends to be transient and self-limiting urinary dip stick for glycosuria and random blood sugar level
• Hyperthyroidism (0.65%-3%)57 • Use DS specific growth charts
• T1DM
a. 4-fold increase28
b. High prevalence of anti-islet antibodies
• Growth
a. Lower height of 2 standard deviations below
general population
b. Reduce height velocity22

(Continues)
LAGAN et al. |
      1099

TA B L E 1   (Continued)

Organ Issues Management

Respiratory issues • Recurrent lower respiratory tract infection • Immunisations up to date in accordance with local guidelines
a. 42% of all admissions72-74 • Recommend pneumococcal23 and annual influenza
▪. More severe illness vaccination
▪. Prolonged hospital stay • Consider prophylactic antibiotic if recurrent chest infections
▪. Increase risk of ICU • RSV prophylaxis specially if other comorbidities77
▪. Requiring ventilatory support with RSV • Feeding Eating Drinking Swallow (FEDS) assessment if
• Chronic Rhinitis persistent respiratory symptoms
• Pulmonary aspiration
Ear, Nose and • Hearing loss −38%-78%84 • Neonatal Hearing screening for sensorineural hearing loss
Throat issues a. OME most common cause of conductive loss • Audiology assessment annual until 5 years of age followed by
▪. 93% of children age 1 year biannual assessment-AAP & DSMIG13,14
▪. 68% by 5 years85 • Chronic rhinitis—steroid therapy and a course of antibiotic
b. Sensorineural hearing loss therapy
▪. 60% unilateral88 • Stridor or recurrent episodes of croup warrant Ear Nose and
▪. 4% infants Throat Specialist review.
▪. 20% in young persons and adults88
• Chronic Rhinitis
a. Secondary to anatomical differences84,86
• Structural anomalies
a. Subglottic stenosis
▪. Lead to recurrent episode of croup
b. Laryngomalacia
c. Tracheomalacia
d. Bronchomalacia
e. Tracheal bronchus (20%)72
Sleep Disordered • Increased incidence 20%-80% • Polysomnography for every child with DS by age 4-AAP14
Breathing • Myriad of symptoms-snoring, restless sleep, flexed • Annual screening of children from infancy to 3-5 years with
forward position, daytime somnolence, behavioural pulse oximetry-RCPCH
changes • Low threshold for investigating old children if symptomatic
Haematology and • Neonatal • Full blood count (FBC) and smear are performed in the
Oncology a. Thrombocytopenia neonatal period
b. Polycythaemia(99 • Annual FBC and ferritin to assess for iron deficiency
c. TAM 10%-15%7 annually-AAP14
▪. Clinical features; hepatosplenomegally, bleeding,
petechiae, pericardial and pleural effusion, and
rash
▪. >10% blasts and GATA1 mutation7
▪. >80% undergo spontaneous remission
▪. 20% will develop AML100,102
• Childhood
a. AML
▪. Presents < 5 years
▪. Preceded by slowly progressive myelodysplastic
syndrome
▪. GATA1 mutation
▪. Acute megakaryoblasts responsive to
chemotherapy
▪. 5-year survival rate at 80%
b. ALL
▪. No associated preleukaemic phase
▪. Profile of ALL in children with DS does not differ
▪. Precursor B cell ALL is the predominant form
▪. Hypodiploidy and chromosomal translocations are
less common (~ 20%)

(Continues)
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1100       LAGAN et al.

TA B L E 1   (Continued)

Organ Issues Management

Immune function • Children with DS are an increased risk of infection • If history of recurrent infection low threshold for immune
a. Particularly by respiratory tract infections, work up including:
▪. high incidence of hospitalisations, a. T/B cell subset
▪. prolonged duration b. Vaccination titres
▪. increased severity c. Immunoglobulins
b. Mortality from sepsis is > 30%71 d. Immunology review
c. 12 times increased risk for mortality104 e. Prophylactic antibiotics
• Adaptive immunity dysfunction • Immunisation is up to date with local schedule
a. Reduced ranges of T and B cell lymphocytes
subsets from infancy 106
b. A smaller thymus size
c. Reduced naïve T-cell and regulatory T-cell
numbers noted 107
d. Suboptimal antibody response to vaccinations
108-110

e. Pro-inflammatory cytokines are

dysregulated.111,112
• Innate immune dysfunction
a. Abnormal neutrophil chemotaxis
b. Defective phagocytic activity have been
reported113
Renal Issues • Renal impairment not been a typical association. • Renal imaging if
• Congenital anomalies (4%) a. abnormal antenatal imaging
a. 4-5 times higher121 b. evidence of recurrent urinary tract infections
b. Frequent abnormalities include: c. abnormal urea and creatinine
▪. posterior urethral values
▪. pyelectasis and mega ureters,
▪. renal hypoplasia,
▪. horseshoe kidney or renal ectopia122
• Renal function lower than the general population123
a. Prevalence of chronic renal failure 4.5%122
Musculoskeletal • Arthropathy of Down syndrome (A-DS) • Paediatric Gait, Arms, Legs and Spinal (pGALS) assessment
issues a. Prevalence of A-DS is 8.7-20/1000, 6 times higher part of the routine paediatric assessment.
than JIA.124,125 • Laboratory markers may be normal or elevated.
b. Proximal interphalangeal joints, wrists, • MRI with gadolinium may aid diagnoses if there is clinical
metacarpophalangeal joints and knees are most uncertainty
commonly affected • Evaluating a child for the development of signs and symptoms
c. 30% will respond to first-line therapies124 of AAI
d. High index of suspicion—due to poor verbal skills a. Comprehensive history
and altered pain expression b. Neurological examination
• 20% will experience orthopaedic problems c. Flexion extension lateral C spine radiography for
secondary to joint laxity and hypermobility.44 symptomatic children
• Atlanto-axial instability (AAI) • Orthotic supports to prevent the consequences of pes planus
a. Symptomatic AAI occurs when a displaced • Low threshold for preforming hip x-ray
odontoid process impinges on the spinal cord. a. Limp ( also consider FBC)
b. Can present with significant neurological findings b. Refusing to weight bear
including spinal compression or death128 c. Not walking by 2 years
c. AAI occurs in 1%-2%
• High incidence of other orthopaedic problems
secondary to joint laxity
a. Foot deformities
▪. Pes planus 70%-90%125
▪. Hallux valgus
▪. Syndactyly
b. Scoliosis-5%,125
c. Hip instability 1%-7%130
▪. Evolve into habitual dislocation to persistent
subluxation and eventually fixed dislocation.
d. Patellofemoral instability
e. Slipped capital femoral epiphysis

(Continues)
LAGAN et al. |
      1101

TA B L E 1   (Continued)

Organ Issues Management

Ophthalmology • Increase risk of ophthalmological issues with age • Neonatal examination to rule out congenital anomalies•
a. 38% of children less than 1 year Ophthalmological assessments from 2 years of age
b. 80% aged 5-12 years.3 biannually-AAP, DSMIG13,14
▪. Increased incidence of refractive errors • Prior to age 2, frequent assessment assessing visual
▪. Oblique astigmatism behaviour and strabismus
▪. Esodeviation strabismus
▪. Poor visual acuity
▪. Cataracts
▪. Blepharitis
▪. Nystagmus 30% 133
Dermatology • Increased prevalence of • Systemic examination to include careful examination of the
a. 36% of seborrheic dermatitis.136 skin and refer to dermatology as required.
b. pityrosporum folliculitis
• Alopecia areata ranges from 1% to 11%137
a. associated with other autoimmune conditions
including vitiligo
• Oral manifestations including macroglossia, fissured
tongue and geographical tongue occur in 80% of
patients.135
• Increased risk of oral candida infections.
• Syringomas occurs 30 times greater
• Other rare conditions such as milia like calcinosis
cutis occur on the hands and feet

Abbreviations: ALL, Acute Lymphoblastic Leukaemia; AML, Acute Myeloid Leukaemia; ASD, Atrial Septal Defect; AVSD, Atrioventricular septal
Defect; CHD, Congenital Heart disease; ECG, Electrocardiogram; EEG, electroencephalogram; OME, Otitis media with effusion; PFA, plain film
radiograph; PGALS, Paediatric Gait, Arms, Legs and Spinal; PH, Pulmonary hypertension; PPHN, Persistent Pulmonary hypertension of the newborn;
TAM, Transient abnormal myelopoiesis; TFT, Thyroid function testing; TPO AB, Thyroid Peroxidase antibodies; VSD, Ventricular Septal Defect.

marginally increased compared to the general population.16 CHD in
DS is more commonly associated with females particularly AVSD
19,20
and VSD. Where CHD is present the five-year survival rates in
children with DS is 92% compared to 94.2% in children with struc-
turally normal hearts. Mortality was highest for those with CHD and
other extra-cardiac malformations, with 93% of deaths occurring in
the first year of life. Mortality of children with DS and CHD com-
16
pared to children with normal chromosomes and CHD was similar.
Visootsak et al compared the neurodevelopment of children at two
years of age with DS and AVSD compared to age-matched controls
with DS without AVSD and a delay in all domains was noted, only the
21
motor domain was statistically significant.
Persistent pulmonary hypertension of the newborn (PPHN)
has an incidence of 5%-34% in the DS population compared to
9,17
0.1% in the general population. Bush et al reported PPHN in
over 9% (n  =  1242) of infants born with DS, 5% had persistent
pulmonary hypertension at one year. In this study, PPHN was con-
sidered to occur in children in the absence of CHD. Weijerman
et al reported an incidence 5.2% (n = 482) of PPHN and 36% had
no associated CHD.9 Martin et al described an incidence of 34%
(n  =  121) of PPHN, with no difference between infants with DS
and without CHD. 22 PH was associated with a longer duration of
hospital stay, increased need for ventilation and requirement for
nitric oxide therapy. 22
The presence of CHD increases the likelihood of developing
pulmonary hypertension (PH) and is associated with increased
morbidity and mortality. 23 Children with uncorrected septal de-
fects will develop shunting of systemic blood to the pulmonary
circulation leading to pulmonary arterial hypertension. This oc-
curs post-surgical correction in some complex cases. Bush et al
reviewed the risk factors for developing later PH in children with
DS (n = 284), 44.8% were associated with CHD, 17.9% by respira-
tory causes. 23
The high incidence of PPHN and PH in infants and children
with DS is likely secondary to abnormalities in pulmonary vas-
culature development, impairment in regulation of vascular tone
and impaired vascular endothelial function. 2,17,23 In CHD there is
increased exposure to left to right shunt flow which can cause a
sheer stress on the endothelium and induce endothelial dysfunc-
tion. Children with DS and CHD have an increased preponderance
to develop PH than children with CHD without a background of
DS. 22
Adults with DS have a low incidence of atherosclerotic disease
and appear to have a reduction in the development of atheroma
and atherosclerosis. Systolic and diastolic blood pressures are
measured to be lower in the DS population. With adults >30 years
the diagnosis of hypertension and use of antihypertensive medica-
tion is much lower than the general population. Hence, the rates of
coronary artery disease in this population are significantly lower
than the general population. 2,24 However, adults with DS and with
and out CHD are at increased risk of valvular disease. Adults who
have previously had a surgical repair for AVSD are at increased
 |
1102       LAGAN et al.
risk of Eisengmenger syndrome and/or left ventricular outflow
obstruction with Aortic valve dysfunction. Serial cardiology fol-
low-up postcorrective surgery is essential. 25 Vis et al, noted 77%
(n = 138) adults without CHD had mild to moderate regurgitation
in one or more valves; therefore, it is important for opportunistic
cardiovascular examination at medical reviews with prompt refer-
ral for echocardiogram if necessary. 26,27
2.1 | Neurodevelopmental
Down syndrome is the most common single cause of intellectual
disability, and there is an association with neurodevelopmental
disorders such as autistic spectrum disorder (ASD) and attention
deficit hyperactivity disorder (ADHD). The prevalence of ASD in
children with DS is significantly higher in the DS population (10%-
18%) compared to 1% in the typically developing population. 28
Although likely to be more evident in individuals with severe intel-
lectual impairment, all children with DS are an increased risk of
ASD. It has been suggested individuals with DS and autism spec-
trum disorder have a different phenotypic presentation; with less
28,29
social withdrawal. Intellectual disability (ID) is synonymous
with DS; however, levels of impairment can vary from a mild in-
30
tellectual disability to severe or even profound, Van Wouwe
et al reviewed the cognitive ability of children with DS in Dutch
schools, the level of cognitive disability was mostly moderate,
43%; however, the distribution was wide with 30% severe, 10%
profound and 17% mild. 31,32 Genetic and environmental factors
must be taken into consideration. However, further mechanisms
must exist. Over eighty conditions are associated with trisomy
21, but all do not occur within the one individual thus epigenetic
differences are likely to be involved. 33,34 Visuo-spatial processing
and perception are relative strengths in people with Down syn-
drome, where verbal short term memory appears to be an area of
difficulty. 22,35 This variation in the level of intellectual disability
can prove challenging when counselling families. A few studies
have looked at the impact of congenital heart disease, structural
GI abnormalities and infantile spasms on the neurodevelopmental
outcome on children with DS. 34,36,37 Studies are small in number. A
diagnosis of CHD and infantile spasms appears to have a negative
impact on all domains of development.
Epilepsy, particularly, infantile spasms have an increased prev-
alence rates of up 2%-13% 38 in children with DS compared to 1%
in the general population. It has been hypothesised the increase
in seizure susceptibility is secondary to genetic changes to ion
39
channel and neurotransmitter function. Infantile spasms (IS) or
West syndrome is the most common epilepsy associated with DS
40
occurring in 2%-5%. West syndrome is an early epileptic en-
cephalopathy characterised by epileptic spasms, hypsarrhythmia
pattern on EEG and development regression, typically present-
ing at 6-8  months of age. The first line of treatment in children
without Tuberous sclerosis is high dose prednisolone. Early treat-
ment is associated with improved outcomes. Children without
DS and idiopathic IS have relapse rate of 10%-20%. However,
Sanmaneechai et al noted an increased relapse rate in the DS pop-
ulation (57% (n  =  12)) which they suggested may be related to a
long time to initiation of treatment.41 Beatty et al found children
with DS and IS were diagnosed and treated similar to patients with
idiopathic IS, with no statistical differences in age of onset, timing
of diagnosis and acute treatment response. However, the DS co-
hort had a lower risk of developing subsequent epilepsy.40 When
neurodevelopmental outcomes were compared in children with
DS and IS group scored lower on all developmental domains when
compared to children with DS without IS. 36 Sanmaneechai et al
reported 5% (n = 8) of their cohort had comorbid autistic spectrum
disorder (ASD).41
Children and adults with DS are at increased risk of other sei-
zure types as well as IS. This may be related to hypoxic ischaemic
events in those with significant CHD or from perinatal insults
on a background of an increased genetic susceptibility.40 Elderly
patients with DS particularly with Alzheimer Diseases have an
increased susceptibility to develop late-onset myoclonic  epi-
lepsy  (LOMEDS). The association of generalised  epilepsy  with
elderly DS represents an epiphenomenon in evolution which is
associated with a progressive deterioration of cognitive and motor
functions.42
An increased prevalence with Moya-Moya syndrome in indi-
viduals with Down syndrome has been noted of up to 26-fold.43
Moya-Moya is a chronic, occlusive, cerebrovascular disorder char-
acterised by the progressive stenosis of the internal carotid arter-
ies and circle of Willis, with concomitant formation of tortuous
arterial collateral vessels at the base of the brain. It can present
with cerebral ischaemia and stroke. Therefore, it is imperative
prompt assessment of patients presenting with new focal neu-
rological deficits, even if transient, to be assessed by MRI and
MRA.43 The association between Moya-Moya and DS is poorly
understood. It is hypothesised it may be secondary to a genetic
predominance to abnormal vasculature or to an autoimmunolog-
ical pathophysiology.44
2.2 | Gastrointestinal
Children with DS are at an increased risk of structural and func-
tional abnormalities of the gastrointestinal (GI) system. After con-
genital heart disease (CHD), congenital anomalies of the GI system
are most frequently reported with a prevalence of 3%-13%.45
Duodenal atresia (DA) is the most common GI anomaly and 25% of
infants born with DA also have a diagnosis of DS and other anoma-
lies in 68%.46 The prevalence of DA in children with DS has been
estimated as 1%-5%, this is supported by a large study of 1892
infants born with DS in North America.47 Anal stenosis/atresia
has been documented to be found in 1%-4% of infants with DS.
Oesophageal atresia and trachea-oesophageal fistula is less com-
mon in the DS population but has a higher prevalence than in the
general population of 0.3%-0.8%.47
LAGAN et al.
Hirschsprung's disease is also commonly associated with DS oc-
curring in 1%-3% of infants with DS, and 5% of Hirschsprung's dis-
ease is associated with DS.48 Hirschsprung disease can present with
severe constipation, abdominal distension and acutely with signs of
obstruction, or in the newborn period with delayed passage of me-
conium. There is some evidence that children with Hirschsprung's
disease and DS will have persistent bowel dysfunction postcorrec-
tive surgery with removal of the aganglionic bowel segment with
faecal incontinence and diarrhoea. Short segment Hirschsprung's
disease may be more difficult to diagnose and many not be clinically
45
symptomatic until after 2 years of age.
Constipation is commonly reported in the DS population
through childhood and adulthood likely as a consequence of hypo-
tonia, poor diet and a reduction in physical activity. Constipation
may be a sign of hypothyroidism. An adult survey identified unex-
plained severe constipation in 19% of responders, but this is likely
to be under estimated in clinical practise.49,50 Gastro-oesophageal
reflux and feeding difficulties are common in infants with DS due to
lower truncal tone and oral motor function. Varying rates in breast-
feeding have been reported and maybe relate to societal norms.
Weijerman et al noted a 30% reduction in breastfeeding rates in
the Dutch population whilst Ergaz-Shaltiel et al reported 84% of
infants were fed human milk. 51 Breastfeeding due to its advantages
in stimulating oro-motor development as well as immune properties
should be encouraged in infants with DS.31 Martin et al reported
high proportion of infants admitted to the postnatal ward will need
admission to the neonatal unit for feeding concerns (18% n = 54)).17
Coeliac disease is estimated to have a prevalence of 5%-
52,53
7.5% in the DS population, a ten-fold increase on the gen-
eral population. It presents more insidiously with abdominal pain,
bloating, constipation and behavioural difficulties. The recom-
mendation from the AAP is to review for symptoms of coeliac dis-
ease at each visit, and if indicated investigated with human tissue
transglutaminase (tTG) and endomysial antibodies, with a serum
Immunoglobulin A (IgA).14 However, as constipation is a common
complaint in children with DS and a single negative coeliac screen
will not out-rule coeliac disease for life, repeated screening has
53
been recommend every 2-3 years. Interestingly, by establishing
HDL status and elimination of those who do not carry HLA-DQ2
/8 which occur in 95% and 5% of patients with CD, respectively,
will reduce the numbers needed to screen by 60% by identifying
these high-risk groups. 52-54
2.3 | Endocrine and Growth
Both acquired and congenital thyroid disorders are associated in
individuals with DS. Infants born with DS have a significant in-
creased incidence in congenital thyroid disease, with one study
estimating it to be 26 times higher than the general population. 55
Neonates with DS tend to have higher levels of Thyroid Stimulating
Hormone (TSH) and lower thyroxine. 56 Autoimmune thyroid dis-
ease has a high prevalence in the Down syndrome population and
|
      1103
is associated with the presence of Thyroid Peroxidase (TPO) anti-
body. As TPO antibodies increase with age, autoimmune hypothy-
roidism is more common after the age of 8 years. The presence of
antibodies increases the likelihood that clinical hypothyroidism will
develop over time57,58 Children with DS can also develop AI hyper-
thyroidism more frequently than the general population although
much less commonly than hypothyroidism. 59 Hyperthyroidism oc-
curs in DS population at an increased incidence (0.65%-3%). It is
more commonly seen in adulthood and is a result of autoimmune
process. 57
Subclinical hypothyroidism with elevated levels of thyroid stim-
ulating hormone and normal levels of thyroxine (T4) is the most
common thyroid abnormality noted in children with DS, estimated
between 25.3% and 60%57,60 It tends to be transient and self-lim-
iting.61 Gibson et al performed a longitudinal study of thyroid func-
tion in 103 patients with DS which showed, 70% of children with
evidence of subclinical hypothyroidism had resolved on subsequent
testing.62 Claret et al, reviewed the progress of 53 patients with
subclinical hypothyroidism, the absence of a goitre and thyroid anti-
bodies was associated with a greater rate of spontaneous remission
but the pathophysiology behind this is unclear.61 Tenenbaum et al
reported subclinical hypothyroidism may have clinical sequalae such
as hypotonia.63Trials of early thyroxine treatment in children with
DS have not shown improvements in neurodevelopmental outcomes
later on in life.64
The current recommendation from the DSMIG UK & Ireland
guidelines is a TSH  <  10  mU/L or the presence of TPO antibodies
in the presence of normal FT4 and in the absence of clinical symp-
toms does not warrant treatment, but may require more frequent
monitoring of thyroid function. Differing recommendations from
the AAP guidelines and DSMIG UK & Ireland exist, the AAP recom-
mend annual TFTs, whilst the European group recommend annual to
5 years followed at least biannually.13,14 No recommendation on the
appropriate course of action or treatment threshold for subclinical
hypothyroidism exists in the AAP guidelines.14 Due to the frequent
blood sampling required in monitoring TFTS, a group from Scotland
have developed an algorithm using capillary TSH screening which
could be performed in the community.65 However, capillary blood
sampling will not detect hyperthyroidism.
Type 1 Diabetes (T1D) has been shown to be more common in
those with DS in a number of studies.66,67 A Danish study showed
4-fold increase in the DS population than general population, with a
peak incidence at a younger age of 8 years compared with 14 years.68
There is also increased onset of T1 Diabetes in early childhood (be-
fore age 2 or 3 years) in children with DS.4 Better glycaemic control
and lower rates of diabetes-related complications have been re-
ported in those with DS.4,69
Children with DS tend to have a lower frequency of the high-risk
HLA genes compared to the general population with T1DM. Aitken
et al showed high prevalence of anti-islet antibodies in the DS pop-
ulation and increased co-occurrence of autoimmune disorders with
diabetes and thyroid dysfunction in 74%, and coeliac disease and
diabetes 14% in their cohort.4
 |
1104       LAGAN et al.
Children with DS follow a different growth pattern, presenting
with a lower height of approximately of two standard deviations
below the mean, and reduce growth velocities. 22 Growth charts
have been developed for monitoring height and weight of children
with DS.70 Growth should be monitored on these specific growth
charts which are essential to highlight changes in growth velocity
which may be a consequence of underlying medical problems, such
as, feeding difficulties, thyroid dysfunction, coeliac disease and ob-
structive sleep apnoea. Growth parameters are ideally monitored at
each point of contact with the health surveillance team.
The UK and Irish DS specific growth charts clearly reflect the
tendency of excessive weight gain in this study sample particularly
in later childhood. Clinical assessment and monitoring of body mass
index (BMI) are recommended from the age of 2  years. There is a
high prevalence of overweight and obesity in those with DS with
its resultant complications, such as, increased type 2 diabetes, but
this is not inevitable. Thyroid dysfunction should be excluded in
those with marked weight gain. Early and regular guidance regarding
healthy dietary practices, physical activity and avoidance of seden-
tary behaviours should be put in place.
2.4 | Respiratory Problems
Respiratory problems are common in children and adults with DS
due to suboptimal immune function, structural abnormalities and
congenital abnormalities. Children with DS have a 30% increased
risk of sepsis.71 Respiratory tract infections are the most common
cause of admission in children with DS (42% of all admissions) and
72-74
the most common cause of mortality after CHD. Children with
DS have a higher incidence of acute lung injury with lower respira-
tory tract infections compared to controls.72 LRTI and CHD remain
important causes of mortality and morbidity in children with DS.75
A recent metanalysis by Beckhaus et al, highlighted children with DS
had a significantly higher risk of severe RSV infection compared to
children without DS with a longer and more severe illness with pro-
longed hospital stays and increase risk of ICU admission and requir-
76
ing ventilatory support. This and other recent studies suggest the
introduction of RSV prophylaxis in this high-risk population.77 The
risk of hospitalisation with RSV of children with DS is at a 6.1-8.7-
fold increase in comparison to children without DS.78
Tracheal bronchus is a common congenital abnormality in chil-
72
dren with DS occurring in up to 20% of patients. This occurs when
the right bronchus develops from the trachea leading to persistent
right upper lobe atelectasis and pneumonia.74 Tracheomalacia and
bronchomalacia are common in DS and can cause noisy breathing,
wheeze and stridor which may mimic asthma and croup.74 Bertrand
et al found 50% of children with DS undergoing a fibre-optic bron-
choscopy had laryngomalacia, and many had associated CHD.79
80
Increased rates of subglottal stenosis are also recognised.
Chronic rhinitis is commonly seen in patients with DS; however,
atopic conditions such as eczema, food allergies and hay fever are
less frequently diagnosed. Wheeze is commonly reported by parents
and treated unsuccessfully as asthma.74,81 The high incidence of
wheeze in children with DS is likely to be related to the associated
structural abnormalities as it is recognised children with DS have less
atopy. It may be associated with gastro-oesophageal reflux.
There is an increased prevalence of pulmonary aspiration in
the DS population which has serious medical consequences and in-
creases the likelihood of developing a lower respiratory tract infec-
tion. It is commonly associated with infants and young children but
is likely to be persistent and under recognised. Pulmonary aspiration
can lead to chronic respiratory symptoms and pulmonary hyperten-
sion. Chest radiographs may be normal or show mild bronchial wall
thickening with significant consolidation or atelectasis. Jackson et al
reviewed 158 patients with DS, 56.3% had evidence of aspiration of
which was silent in 90.2%. Thickened liquids were the most effective
change to feeding technique.82
2.5 | Ear, Nose and Throat
Children with DS have a high prevalence of ear, nose and throat
abnormalities (ENT) which can have a significant impact on quality
of life. Issues can vary from recurrent rhinorrhoea to otitis media
with effusion, obstructive sleep apnoea and hearing loss. This is
secondary to a combination of low tone, small mid face, narrow ear
canals, macroglossia, adenotonsillar hypertrophy as well as immune
dysfunction.83
Hearing loss and recurrent ear infections are the primary reason
for referral to the ENT services. Overall children and adults with
DS have a significantly higher incidence of hearing loss (38%-78%)
than the general population (2.5%). 84 Otitis media with effusion is
the most common cause of conductive hearing loss in children. Barr
et al note 93% of children with Down syndrome had otitis media
with effusion (OME) aged 1 year and decreased to 68% by the 5th
year of life. 85 The high prevalence of OME is felt to be related to the
difference in Eustachian tube length. A more cylindrical shape and
smaller in width and that can be associated with an abnormal inser-
tion point. Secondary to the generalised hypotonia in children with
DS can have poor function of the tensor veli palatine muscle of the
palate, which is responsible for opening and closing the Eustachian
tube resulting in the development of otitis media with effusion. 86
Stenotic ear canals can occur of up to 40%-50% of infants with DS
and 80% are associated with OME. 84,86 The treatment of OME is
the placement of positive pressure equalisation tubes (grommets)
and or hearing aids. 87 Many children will need recurrent grommet
insertion (>50%). 84 Grommets can be complicated by small narrow
ear canals and otorrhea and are extruded at an increased rate to the
general population. Sensorineural hearing loss (SNHL) occurs in 4%
of infants on newborn hearing screening, 88 and 60% are unilateral.
However, the incidence of SNHL increases with age, with a preva-
lence of 20% in young people and adults with DS. 83 Children with
DS due to their cognitive delay are at an increased risk for speech
and language delay therefore it is important to assess and monitor
for hearing loss and treat as appropriately.
LAGAN et al.
Children with DS have an increased incidence of chronic rhinosi-
nusitis. This is felt to be related to the anatomical differences with
mid face hypoplasia and narrow nasal passages which leads to mucus
pooling and stagnation which drives infection only to increase mu-
cous production in addition to a dysfunctional immune function.86,88
Treatment may involve trial of nasal wash outs, nasal steroids, an-
tihistamine, topical decongestants and antibiotic therapy. If there
is evidence of adenoid hypertrophy, adenoidectomy may improve
symptoms.86,88
An increased incidence of subglottic stenosis is recognised in
children with DS. It is generally mild or asymptomatic but may pres-
ent as recurrent episodes of stridor and croup or as a difficult in-
tubation. A smaller endotracheal tube is often required in children
86,88
with DS.
2.6 | Sleep disordered breathing and
Down syndrome
Incidence of sleep disordered breathing (SDB) in the general pae-
diatric population is estimated to be 2%89 and associated with
detrimental effects on behaviour and cognition. However, there is
a higher incidence in the DS population throughout all ages.90 The
increased incidence maybe related to anatomical differences with
midface hypoplasia, macroglossia, adenotonsillar hypertrophy and
muscle hypotonia as well as with an increased prevalence of phar-
yngo-laryngomalacia stenosis. Comorbidities such as obesity, hy-
pothyroidism and gastro-oesophageal reflux disease increase the
likelihood of developing sleep disordered breathing.91 The preva-
92,93
lence of sleep disorders is 20%-80% in children with DS. Maris
et al in 2016 showed a prevalence of OSA of 66.4% in their cohort of
89,93
children with DS who were referred with clinical concerns. Hill
et al performed polygraphy on 188 children with DS under the age
of 4 as per the AAP guidelines and estimated a prevalence of 44%,
89,94,95
of which 14% had severe OSA. Severity was not predicted by
age, tonsillar size or BMI centile.
Symptoms of sleep disordered breathing in children with DS
can present with a myriad of symptoms such as heavy breathing,
snoring, restless sleep, unusual sleeping position including sleep-
ing flexed forward, frequent waking and daytime somnolence.96
Although it is important to note child may have no sleep symp-
toms but display changes in behaviour, attention and academic
performance.97 Children with DS are at increased risk of devel-
oping adverse complications of OSA and 60% have a congenital
heart disease increasing the likelihood of developing pulmonary
97
hypertension. The AAP recommend universal screening for ob-
structive sleep apnoea (OSA) with a polysomnography by age 4 in
all children with DS regardless of symptoms.14 There is a poor cor-
relation between parental reported symptoms and PSG results14
leading the Royal College of Paediatrics and Child Health to rec-
ommend annual screening of children from infancy to 3-5  years
with pulse oximetry.13
|
      1105
Screening for OSA using ambulatory pulse oximetry has a sensi-
tivity of 96% and specificity of 52% in children with DS. This has the
potential to greatly reduce the number of children needing full PSG
in order to make the diagnosis.94
The treatment of OSA in children remains difficult. AAP rec-
ommends adenotonsillectomy in first instance for all children with
OSA and tonsillar hypertrophy. A surgical approach is successful in
up to 80% of children. However, in a chid with DS there are many
confounding variables including the midfacial anatomy and tonal
problems which add to the aetiology of OSA. Maris et al reviewed
the outcomes of adenotonsillectomy in children with DS and OSA
and although significant improvement in OAHI was noted, persistent
OSA was found in 47%.89 Continuous positive airway pressure ven-
tilation is used in children with severe OSA which is persistent after
adenotonsillectomy or who surgery is not feasible. This is tolerated
poorly with estimated compliance rates of approximately 50%.96,98
Mild OSA is often medically treated with intranasal steroids and
Montelukast but the true efficiency of medical management has not
been established.98
2.7 | Haematology and oncology
Children with DS have an increased risk of myeloid leukaemia and
other haematological problems.99 They may not always be sympto-
matic so a full blood count in the first few days of life is important.
Thrombocytopenia and polycythaemia are commonly seen in the
neonatal period. Thrombocytopenia is not always an indicator of se-
rious illness but rather a feature of DS but sepsis must be outruled
as these infants have are at increased risk.5 Neonatal polycythaemia
occurs with a 20-fold excess in DS than the general population.99 It
occurs independently of cyanotic heart disease and often resolves
by the 8th week of life. Polycythaemia is almost three times more
likely to occur if thrombocytopenia exists.99
Transient abnormal myelopoiesis (TAM) is one of the most clini-
cally significant abnormalities to occur in the neonatal period in DS
with an incidence of 10%-15%.7 TAM is characterised by increased
circulating blast cells which contain a mutation in the key haemato-
poietic transcription factor GATA1. TAM may be asymptomatic in si-
lent TAM or be symptomatic with a mortality rate of up to 20%.6,7,100
Clinical features of TAM include hepatosplenomegaly, bleeding and
petechiae, effusions (pericardial and pleural) and skin rash and can
lead to significant hepatic fibrosis. TAM may present in foetal life
with hydrops fetalis.6,7 TAM is characterised by an increased number
of blast cells in the peripheral blood. However, many asymptomatic
children with DS with have occasional blasts on blood film as a ne-
onate. There is poor consensus internationally on the percentage
blast threshold for a diagnosis of TAM. The Oxford Imperial Down
Syndrome Cohort (OIDSC) defined TAM as >10% of peripheral blasts
and a GATA1 mutation7 and had an incidence of 8.5% (n  =  200).
The criteria identified all neonates with clinically significant TAM.
Silent TAM was regarded as <10% blasts cells and a positive GATA1
 |
1106       LAGAN et al.
mutation and these infants were asymptomatic. The majority of
cases (>80%) will undergo spontaneous resolution of both clinical
and laboratory abnormalities by 3 months of age.6,7,100 Those infants
with severe or life threatening symptoms may be treated with low
chemotherapy, cytarabine 1-1.5 mg/kg/day either intravenously or
101
subcutaneously.
Retrospective studies estimate that 20% of neonates with clin-
ically significant TAM will develop myeloid leukaemia of DS (ML-
DS).6,100,102 In most cases, there is an apparent remission before the
development of ML-DS. All cases of ML-DS have a GATA1 mutation,
7
therefore TAM is clonal neonatal preleukaemic disorder. The fac-
tors which predict the development of ML-DS from TAM are un-
known. However, as silent TAM can also progress, it is unlikely to
7
be related solely to the size of the clonal mutation. Hence children
who have had neonatal TAM are monitored for evolving clinical and
laboratory signs of ML-DS. There is no evidence to support the use
of cytarabine in neonates solely to prevent later development of
101
ML-DS and is not recommended.
ML-DS is a classified subtype of acute myeloid leukaemia
which only occurs in children with DS. It typically presents in the
first five years of life and is preceded by a slowly progressive my-
elodysplastic prodrome of 4-24  months, a GATA1 mutation and
megakaryoblastic lineage. These blasts have a similar immuno-
phenotypic profile with typical megakaryocytic morphology and
co-expression of stem/progenitor markers of those seen in TAM.
ML-DS blasts are highly sensitive to cytarabine with 5-year sur-
vival rates at 80%. 6,7,99,100,102
Children with DS have a 20-fold increased risk of developing
Acute Lymphoblastic Leukaemia (ALL). There is no associated pre-
leukaemic prophase in DS-ALL and the profile of ALL in children with
DS does not differ from that of the general population. However,
children with DS-ALL have poor outcomes compared to the general
population.6 Precursor B cell ALL is the predominant form and T-cell
ALL is very rare. Hypodiploidy and chromosomal translocations are
less common in the DS children (~20%) as compared with the gen-
eral paediatric population (60%).6,99,102 Although children with DS
are at an increased risk of leukaemia, solid tumours are much less
102
common.
In older children, DS is associated with increased mean red
cell volume (MCV) and haematocrit. There are generally normal
B12 and folate levels. There is some data that haemoglobin levels
maybe higher in children with DS. It has been hypothesised that
it may be a reflection of enhanced erythropoiesis in response to
impaired oxidative metabolism.99 Due to poor dietary habits, iron
deficient anaemia is common in children and young people with
DS and may have a negative impact on development and general
well being.103
2.8 | Immunology
DS is the most common genetic syndrome associated with abnor-
mal immune function and immune defects. Children with DS are an
increased risk of infection, particularly by respiratory tract infec-
tions, with high incidence of hospitalisations, prolonged duration
and increased severity.73 Mortality from sepsis is 30% greater in
patients with DS in comparison to the children without DS who
are admitted for treatment of sepsis.71 Hill et al noted a 12 times
increased risk for mortality due to infections in individuals with
DS.104 The increased susceptibility to infections in children with
DS is associated with anatomical factors such as airway and ear
anomalies and gastro-oesophageal reflux, as well as immune fac-
tors thus often manifest as recurrent respiratory tract infections.
Respiratory tract infections are associated with more severe ill-
ness in individuals with DS suggesting dysfunction in the adaptive
immunity.105 Immune dysregulation has been noted with reduced
ranges of T and B cell lymphocytes subsets from infancy.106 A
smaller thymus size in comparison to age-matched controls with re-
duced naïve T-cell and regulatory T-cell numbers noted.107 Kuster et
al found a suboptimal antibody response to vaccinations. 108-110 Pro-
inflammatory cytokines are dysregulated in patients with DS.111,112
The innate immune system also appears to be dysfunctional in in-
dividuals with DS. Abnormal neutrophil chemotaxis and defective
phagocytic activity have been reported.113,114
Immune dysregulation is important feature of DS such as reduced
T and B lymphocyte counts,105,115 altered serum cytokines111,116 and
suboptimal antibody responses to immunisation108,109,117 Hence, a
diagnosis of DS implies a primary immunodeficiency and children
should receive annual influenza vaccination as well as 23-valent
pneumococcal vaccination from 2  years with consideration to the
Meningococcal ACWY should be given in addition to the recom-
mended immunisation guidelines.118 The longer term immunogenic-
ity of vaccinations is unclear at present, boosters maybe required.
Paliviziumab prophylaxis in children with DS under 2  years of age
may be efficacious and safe in preventing RSV related complications
in this vulnerable population.75,77
The phenotype of immunodeficiency most often resemble com-
mon variable immunodeficiency (CVID) with sinopulmonary infec-
tions and hypogammaglobulinaemia. Individuals with DS have been
noted to have low numbers of memory B cells with reduced prolif-
eration similar to that of CVID.119 The defects in B cell memory may
offer an explanation to why children with DS have recurrent infec-
tions to the same pathogen. Therefore, some patients with DS and
recurrent infections warrant treatment with long term prophylaxis
and a small proportion of patients ultimately need immunoglobulin
replacement therapy. The presence of immune dysfunction, particu-
larly B cell, in children maybe responsible for the increased associa-
tion with autoimmune dysfunction.120
2.9 | Renal
Renal impairment in children with DS has not been a typical associa-
tion. It has been reported 4% of children with DS will have congeni-
tal anomalies of the kidney and urinary tract (CAKUT). There is an
increased prevalence CAKUP in the DS population, up to 4-5 times
LAGAN et al.
higher compared to the general population.121 The most common
urinary anomalies generally are obstructive in nature. Frequent ab-
normalities include posterior urethral values, pyelectasis and mega
ureters, as well as renal malformations such as renal hypoplasia,
horseshoe kidney or renal ectopia.122 as well as hypospadias, cryp-
torchidism and a smaller penis. Renal imaging is generally reserved
for those children with abnormal antenatal imaging, evidence of
recurrent urinary tract infections or abnormal urea and creatinine.
Even in the absence of renal anomalies, the renal function in chil-
123
dren with DS is assumed to be lower than the general population.
Yamakawa et al report children with DS (n  =  108) had 80% the
kidney function of health Japanese children. Although a variety of
urological abnormalities and glomerulopathies have been report in
children with DS, no specific glomerulopathy has been associated.
However, some autopsy studies in patients with DS found typical
findings such as glomerular microcysts, tubular dilation and imma-
ture glomeruli.123 Metabolic abnormalities such as hyperuricosuria
122
and hypercalciuria have been noted. The prevalence of chronic
renal failure has been reported at 4.5%.122 Cases of end-stage renal
failure have been documented.122
2.10 | Musculoskeletal
Children with DS have an increased association with autoimmune
disorders and an association with arthropathy. The term arthropa-
thy of Down syndrome (A-DS) has been coined to describe the
unique musculoskeletal and immunological features associated with
Juvenile idiopathic arthritis (JIA) in children with DS. Prevalence of
A-DS is 8.7/1000, 6 times higher than JIA. However, Foley et al re-
cently documented a prevalence of 20 per 1000 in a cohort of 503
124,125
children with DS, 7% had A-DS. At present guidelines do not
screen for arthropathy; however, there is a movement to include a
Paediatric Gait, Arms, Legs and Spinal (pGALS) assessment as part
of the routine paediatric assessment. Children with A-DS initially
present with a polyarticular, or oligoarticular disease, with joint
swelling, and functional limitation of both small and large joints in a
126
symmetrical fashion. The proximal interphalangeal joints, wrists,
metacarpophalangeal joints and knees are most commonly affected.
Laboratory markers may be normal or elevated. MRI with gadolin-
ium may aid diagnoses if there is clinical uncertainty. There is a poor
association with ocular complications. Although most children will
need therapy with second line disease modifying agents, approxi-
mately 30% will respond to first-line therapies alone.124 Foley et al
reported a delay in diagnosis, therefore children were presenting
with significant joint damage and disability at time of diagnosis, with
125
bone erosions evident on x-ray in 42% of patients. A high index of
suspicion is required as children with DS may have poor verbal skills
and altered pain expression.
Approximately 20% of children with DS will experience or-
thopaedic problems127 as a consequence of joint laxity and
hypermobility. Atlanto-axial instability (AAI) is one of the most se-
rious complications as it can present with significant neurological
|
      1107
findings including spinal compression or death.128 AAI occurs in
1%-2% of individuals with DS. AAI occurs due to an increased
laxity of the muscles and ligaments, especially the transverse alar
ligament, between C1 and C2 vertebrae. Symptomatic AAI occurs
when a displaced odontoid process impinges on the spinal cord.
Permanent or sudden damage to the spinal cord rarely occurs
without previous neurological symptoms. Treatment for AAI is
limited to surgical stabilisation of the atlanto-axial complex and is
recommended for patients with an atlanto-axial distance greater
than 10 mm. Red flags for symptomatic AAI include as follows: de-
velopment of neck pain, torticollis, reduced range of neck move-
ments, deterioration of gait, frequent falls, increased fatigability
on walking, deterioration of manipulative skills, change in sphinc-
ter control and positive findings on neurological exam suggestive
of an upper motor neurone lesion including increased tone and
deep tendon reflexes.125,128 Previously, radiological screening was
considered to be the best tool for the early detection of AAI; how-
ever, it is now recognised that x-rays are unreliable and have a low
correlation with clinical indicators of AAI, low reproducibility and
poor sensitivity. A normal radiography does not out-rule a child
will not develop AAI in the future, nor does a positive radiograph
guarantee an actionable level of risk. Evaluating a child for the de-
velopment of signs and symptoms by comprehensive history and
neurological examination is now the mainstay of screening for AAI
with symptomatic children being assessed further with flexion ex-
tension lateral C spine radiography.125
Children with DS have a high incidence of other orthopaedic
problems including foot deformities, scoliosis and hip instability sec-
ondary to joint laxity. Historically, 70% of the DS population have
evidence of pes planus, but Foley et al report a nearly universal inci-
dence(91%).129 Other foot problems include hallux valgus and syn-
dactyly. 1%-7% of children have hip instability.130 Hypermobility of
the joint can evolve into habitual dislocation to persistent sublux-
ation and eventually fixed dislocation which can result in the loss
of independent mobility. Surgical intervention is recommended for
patients with evidence of dislocation and subluxation. It can be dif-
ficult to manage surgically given to the underlying pathophysiology.
International guidelines from the United States and Netherlands
recommend annual hip screening to enable early detection of hip
involvement.131
Scoliosis may also occur in adolescence with DS with an inci-
dence 5%,125 an association with previous thoracotomy for treat-
ment of congenital heart disease has been noted. Patellofemoral
instability and slipped capital femoral epiphysis occurs more
often in children with DS. Early detection and treatment prevents
complications.125
2.11 | Ophthalmology
Children with DS are prone to a number of ophthalmological
disorders which tend to increase with age ranging from 38% of
children less than 1 year to 80% aged 5-12 years. 3 Children with
 |
1108       LAGAN et al.
DS, in contrast to the general population will have increased in-
cidence of refractive errors as a consequence of a failure of em-
metropisation. Oblique astigmatism occurs more frequently in
DS and may increase with time as consequence of the palpebral
fissures. Esodeviation strabismus is common in children with
DS. Poor visual acuity is associated with DS. Ocular pathology
should be outruled. Cataracts and blepharitis are common also.132
Nystagmus is present in 30% of patients.133 Keratoconus occurs
in an increased incidence in young people with DS. Detailed cor-
neal examinations should be completed in patients with DS to de-
tect keratoconus earlier, implement treatment and avoid further
visual impairments.134Hence, regular ophthalmological assess-
ments are necessary as outlined by the AAP guidelines and the
DSMIG Uk and Ireland annually to 5  years followed by biannual
assessments.13,14
2.12 | Dermatology
DS has been associated with an increased prevalence of atopic der-
matitis (56%) but more recent literature suggests a rate of 1.4%.
using new diagnostic criteria for atopic dermatitis.135 This would
be consistent with a low risk of atopy in the DS population.81 Cater
and Jegasothy found a prevalence of 36% of seborrheic dermati-
tis.136 There is an increased prevalence of pityrosporum folliculitis
in DS, fine monomorphic, pruritic papules and pustules along the
facial hairline and upper back secondary to localised yeast infec-
tion. Alopecia areata ranges from 1% to 11% and has an increased
frequency compared to the general population.137 Alopecia areata
more severe in DS with 2.5% of patients with DS having DS alopecia
totalis and universalis. It is associated with other autoimmune condi-
tions including vitiligo. Psoriasis occurs in an increased frequency in
individuals with DS.138 Oral manifestations including macroglossia,
fissured tongue and geographical tongue occur in 80% of patients.135
There is an increased risk of oral candida infections. Syringomas oc-
curs 30 times greater than in the general population and occur ex-
clusively on the eyelids in DS patients. Other rare conditions such
as milia like calcinosis cutis occur on the hands and feet of children
with DS. Hence, when reviewing children with DS, it is important to
carefully examine the skin.
3 |  CO N C LU S I O N
Children with DS are at an increased risk of numerous multiorgan
comorbidities. Routine ongoing health surveillance is vital. Best
practice guidelines to have been developed to ensure standardised
holistic care for the children and families with DS the guidelines out-
lines by AAP and the DSMIG UK and Ireland enable the early rec-
ognition and treatment of associated medical issues. Thus, quality
of life and life expectancy of individuals with DS has increased rap-
idly in the last few decades. Minor discrepancies still exist presently
between current guidelines. With respiratory disease and infection
an important cause of mortality in this population international con-
sensus is required, together with continual research and develop-
ment into the implications of having a third copy of chromosome
21. Expansion of guidelines to include the growing adult population
with trisomy 21 is being undertaken to continue the high quality care
being delivered.
C O N FL I C T S O F I N T E R E S T
The authors declare no conflict of interest.
ORCID
Niamh Lagan  https://orcid.org/0000-0003-1074-2414
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How to cite this article: Lagan N, Huggard D, Mc Grane F,
et al. Multiorgan involvement and management in children
with Down syndrome. Acta Paediatr. 2020;109:1096–1111.
https​://doi.org/10.1111/apa.15153​