Endocrine, auxological and metabolic profile in children and adolescents with Down syndrome: from infancy to the first steps into adult life

Abstract

Down syndrome (DS) is the most common chromosomal disorder worldwide. Along with intellectual disability, endocrine disorders represent a remarkable share of the morbidities experienced by children, adolescents and young adults with DS. Auxological parameters are plotted on syndrome-specific charts, as growth rates are reduced compared to healthy age- and gender-matched peers. Furthermore, children with DS are at increased risk for thyroid dysfunctions, diabetes mellitus, osteopenia and obesity compared to general population. Additionally, male individuals with DS often show infertility, while women tend to experience menopause at an overall younger age than healthy controls. Given the recent outstanding improvements in the care of severe DS-related comorbidities, infant mortality has dramatically decreased, with a current average life expectancy exceeding 60 years. Accordingly, the awareness of the specificities of DS in this field is pivotal to timely detect endocrine dysfunctions and to undertake a prompt dedicated treatment. Notably, best practices for the screening and monitoring of pediatric endocrine disorders in DS are still controversial. In addition, specific guidelines for the management of metabolic issues along the challenging period of transitioning from pediatric to adult health care are lacking. By performing a review of published literature, we highlighted the issues specifically involving children and adolescent with DS, aiming at providing clinicians with a detailed up-to-date overview of the endocrine, metabolic and auxological disorders in this selected population, with an additional focus on the management of patients in the critical phase of the transitioning from childhood to adult care.

Full text

Endocrine, auxological and
metabolic profile in children
and adolescents with Down
syndrome: from infancy to
the first steps into adult life
Silvia Molinari
1,2
*, Chiara Fossati
1
, Maria Laura Nicolosi
1
,
Santo Di Marco
2
, Martha Caterina Faraguna
2
,
Francesca Limido
2
, Laura Ocello
2
, Claudia Pellegrinelli
2
,
Martina Lattuada
2
, Alessandra Gazzarri
1
, Alessandra Lazzerotti
1
,
Debora Sala
1
, Chiara Vimercati
1
, Giulia Capitoli
2
,
Cecilia Daolio
1
, Andrea Biondi
1,2
, Adriana Balduzzi
1,2
and Alessandro Cattoni
1,2
1
Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy,
2
School of
Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
Down syndrome (DS) is the most common chromosomal disorder worldwide. Along
with intellectual disability, endocrine disorders represent a remarkable share of the
morbidities experienced by children, adolescents and young adults with DS.
Auxological parameters are plotted on syndrome-specific charts, as growth rates
are reduced compared to healthy age- and gender-matched peers. Furthermore,
children with DS are at increased risk for thyroid dysfunctions, diabetes mellitus,
osteopenia and obesity compared to general population. Additionally, male
individuals with DS often show infertility, while women tend to experience
menopause at an overall younger age than healthy controls. Given the recent
outstanding improvements in the care of severe DS-related comorbidities, infant
mortality has dramatically decreased, with a current average life expectancy
exceeding 60 years. Accordingly, the awareness of the specificities of DS in this
field is pivotal to timely detect endocrine dysfunctions and to undertake a prompt
dedicated treatment. Notably, best practices for the screening and monitoring of
pediatric endocrine disorders in DS are still controversial. In addition, specific
guidelines for the management of metabolic issues along the challenging period
of transitioning from pediatric to adult health care are lacking. By performing a
review of published literature, we highlighted the issues specifically involving children
and adolescent with DS, aiming at providing clinicians with a detailed up-to-date
overview of the endocrine, metabolic and auxological disorders in this selected
population, with an additional focus on the management of patients in the critical
phase of the transitioning from childhood to adult care.
KEYWORDS
Down syndrome, hypothyroidism, hyperthyroidism, hypogonadism, diabetes mellitus,
osteopenia, osteoporosis, obesity
Frontiers in Endocrinology frontiersin.org01
OPEN ACCESS
EDITED BY
Anna Di Sessa,
University of Campania Luigi Vanvitelli, Italy
REVIEWED BY
Giorgia Pepe,
University of Messina, Italy
Randall J. Roper,
Purdue University Indianapolis, United States
Laura Chioma,
Bambino Gesù Childrens’Hospital, Italy
*CORRESPONDENCE
Silvia Molinari
s.molinari3@campus.unimib.it
RECEIVED 02 December 2023
ACCEPTED 25 March 2024
PUBLISHED 08 April 2024
CITATION
Molinari S, Fossati C, Nicolosi ML, Di Marco S,
Faraguna MC, Limido F, Ocello L,
Pellegrinelli C, Lattuada M, Gazzarri A,
Lazzerotti A, Sala D, Vimercati C, Capitoli G,
Daolio C, Biondi A, Balduzzi A and Cattoni A
(2024) Endocrine, auxological and metabolic
profile in children and adolescents with
Down syndrome: from infancy to the
first steps into adult life.
Front. Endocrinol. 15:1348397.
doi: 10.3389/fendo.2024.1348397
COPYRIGHT
© 2024 Molinari, Fossati, Nicolosi, Di Marco,
Faraguna,Limido,Ocello,Pellegrinelli, Lattuada,
Gazzarri, Lazzerotti, Sala, Vimercati, Capitoli,
Daolio, Biondi, Balduzzi and Cattoni. This is an
open-access article distributed under the terms
of the Creative Commons Attribution License
(CC BY). The use, distribution or reproduction
in other forums is permitted, provided the
original author(s) and the copyright owner(s)
are credited and that the original publication
in this journal is cited, in accordance with
accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.
TYPE Review
PUBLISHED 08 April 2024
DOI 10.3389/fendo.2024.1348397

1 Introduction
Trisomy 21 is the most frequent chromosomal aberration and
the leading genetic cause of intellectual disability in the general
population (1), with an incidence ranging from 1:700 to 1:1000
among live births and a prevalence of 1:400-1:3000 (2).
As a result of remarkable improvements in the care of affected
children, adolescents and adults over the last decades, the scientific
community has witnessed a dramatic increase in the life expectancy
of people with Down syndrome (DS), currently set beyond the age
of 60 years (3).
Accordingly, it’s pivotal that clinicians involved in the lifetime
care of individuals with DS are provided with proper theoretical and
practical expertise to face the progressively increasing burden of
trisomy-related medical complications.
Thyroid disease, diabetes, obesity, short stature, subfertility and
low bone mineral density account for a significant share of the
medical complications recorded among subjects with DS.
By performing a comprehensive review of published literature,
our objective was to provide clinicians with a detailed and updated
overview of endocrine, metabolic, and auxological disorders
recorded in children and adolescents with DS.
Table 1 and Figure 1 provide a summary of the most frequently
reported endocrine disorders among children and adolescents with
DS, along with additional information about the specificities of each
clinical picture in the setting of trisomy 21.
2 Thyroid function
Thyroid disorders are more frequent in children with DS than
in the general population, with an age-related prevalence ranging
from 4-8% in children to 54% in adults. Individuals with DS
experience a 6-fold greater occurrence of hypothyroidism than
hyperthyroidism. In addition, in patients with DS more
commonly than in healthy controls, autoimmune dysthyroidism
encompasses a dynamic spectrum of disorders, with recurrent shifts
from hypo- to hyperfunctioning gland dysfunctions and vice versa
(4,5).
Firstly, children with DS are prone to develop congenital
hypothyroidism (CH) compared to healthy controls (6). The first
mainstay of prompt detection and treatment of CH is the Newborn
Screening (NBS) program by dry blood spot test (7). The negative
impact of a misdiagnosed congenital hypothyroidism on cognitive
development is well-known; as a variable degree of developmental
delay is typical of DS, early diagnosis of hypothyroidism in
newborns with DS is pivotal (8,9).
In addition, children with trisomy 21 present a higher risk of
developing autoimmune disorders, probably due to syndrome-
related dysregulation of immune tolerance (10). Therefore, both
Hashimoto thyroiditis and Graves’disease are highly frequent in
this population. Epidemiological studies report that anti-thyroid
antibodies are found in 1.3% of otherwise healthy children versus
13-14% of people with DS, highlighting a 10-fold greater occurrence
of autoimmune thyroid diseases (11).
In the following paragraphs we will provide detailed
information about the specificities of each thyroid disorder in the
population of pediatric individuals with DS.
2.1 Congenital hypothyroidism
CH, defined as an increase of Thyroid Stimulating Hormone
(TSH) values with low/normal fT4 and fT3, is usually diagnosed in
the first weeks of life through the NBS programs. The overall
reported incidence of CH in DS is about 1% in Western
Countries, 28 times greater than in healthy children (12).
In this sub-population, gland hypoplasia, which can already be
identified during fetal stage, is the most frequent abnormality (18-
83%) (13). On the other hand, partial or total thyroid agenesia, as
well as ectopic gland or goiter are overall rare findings among
newborns with CH and DS (14,15). Furthermore, in 5-59% of cases,
ultrasound reveals an in situ gland without any dimensional or
morphological defect (12).
The significant occurrence of CH in the setting of anatomically
normal glands has raised questions about the pathophysiology of
congenital impaired thyroid function in DS. Luton et al., by autoptic
analyses on 13 fetuses with DS, highlighted a paucity of follicles,
supporting the hypothesis of a less effective hormonal stimulus (13).
The overexpression of dual-specificity tyrosine-(Y)-
phosphorylation regulated kinase 1A (DYRK1A) gene, located on
chromosome 21, has been identified as a potential pathogenic
factor, playing a detrimental role on thyroid follicle maturation
from the fetal stage onwards (16).
In addition, the incidence of transitory CH is greater among
newborns with DS than in healthy controls. Indeed, in up to 30% of
patients, thyroid function normalizes over time (17). It is likely that
the abovementioned sub-optimal gland function may become overt
during periods of increased metabolism, such as the neonatal
period, concomitant malformations (e.g. cardiopathy), or
perinatal complications. Whenever newborns with DS meet the
criteria for substitutive treatment with L-thyroxine, treatment is
commenced, following the same indications provided for otherwise
healthy infants. Nevertheless, after the first three years of life, when
hormone-dependent development of the central nervous system is
fulfilled, endocrinologists should consider attempting therapy
discontinuation, especially whenever concomitant complications
that may have been negatively affecting thyroid function over the
neonatal stage have been addressed and effectively treated.
Positive predictors of successful L-thyroxine withdrawal are
persistently normal TSH values, lower TSH values at diagnosis and
stable doses of levothyroxine over time (18).
Therapy goals are the same as those for any child with CH: to
achieve TSH within age- and kit-specific reference ranges, tolerating
increased fT4 levels as long as not associated with TSH suppression
(19). Notably, in newborns and infants with DS and congenital
heart disease, increased FT4 levels should prompt a strict
biochemical and clinical follow-up, that could eventually lead to a
reduction of L-thyroxine dose, in order to prevent children from
experiencing cardiac arrythmias and acute complications.
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TABLE 1 Summary of endocrine, auxological and metabolic disorders potentially experienced by children and adolescents with Down syndrome (DS).
Class of
endocrine
disorders
Clinical
picture Occurrence in DS Recommended screening to
promote early detection in DS Treatment in DS
Specificities of the condition in
children and adolescents
with DS
Thyroid
function
Congenital
hypothyroidism 1%
- Dry blood spot on Guthrie card for all
newborns
- TSH at the end of the neonatal period
L-thyroxine, to be started as soon as
possible and always within 14 days
of life
- Up to 30% of cases are transient
- Anatomic findings: in situ gland with
normal volume: 5-59%; gland hypoplasia 18-
83%; goiter: 0-22%; agenetic or ectopic
gland: 0-8%
Autoimmune
hypothyroidism 13-34%
- TSH at 6 months and 12 months of age
and annually thereafter
- Annual thyroid gland palpation and
assessment of potential symptoms
- Thyroid auto-antibodies in case of goiter
or abnormal TFT
L-thyroxine
- Wide variability of effective L-thyroxine
doses have been reported in DS (0.3 to 6.6
mcg/Kg daily)
- Anti-TPO antibodies show a remarkably
better positive predictive value than anti-TG
Autoimmune
hyperthyroidism 0.66%
- TSH at 6 months and 12 months of age
and annually thereafter
- Annual thyroid gland palpation and
assessment of potential symptoms
- Thyroid auto-antibodies in case of goiter
or abnormal TFT
-Anti-thyroid medications;
- thyroidectomy
-radioiodine therapy
- Prolonged administration of anti-thyroid
medications should be pursued, given the
greater occurrence of adverse effects of
surgery (anatomic features) and radioiodine
treatment (risk of secondary malignancies)
in DS subjects
Subclinical non-
autoimmune
hypothyroidism
10-39% TSH at 6 months and 12 months of age and
annually thereafter L-thyroxine
-In asymptomatic individuals, TSH
threshold above which treatment is
recommended is still controversial
- slight upward shift of average TSH levels
in DS compared to healthy controls have
been reported
- In over 70% of cases, TFT normalize
within 5 years
Gonadal
function
Compensated Leydig
cells
dysfunction (male)
Marginally increased LH with normal testosterone
reported in up to 50% of Tanner 5 subjects
No specific monitoring is recommended, as
testosterone levels are commonly normal None
Adolescents with DS often experience
increased LH levels in the setting of normal
testosterone levels (compensated
hypergonadotropic hypogonadism)
Infertility (male) Increased FSH levels have been reported in up to 88-
100% of post-pubertal adolescents with DS No specific monitoring is recommended None
Adults with DS are generally regarded as
infertile, though three cases of spontaneous
parenthood have been reported
Premature
menopause (female)
Up to 88% of women with DS aged 46 to 50 years are
in menopause
Complete assessment of gonadal function in
case of early-onset secondary amenorrhea
Hormonal replacement therapy
if required
Female individuals with DS are regarded as
potentially fertile, but experience a
precocious decrease in oocyte reserve, thus
leading to menopause earlier than healthy
controls (median age: 46 years versus 51-52)
(Continued)
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TABLE 1 Continued
Class of
endocrine
disorders
Clinical
picture Occurrence in DS Recommended screening to
promote early detection in DS Treatment in DS
Specificities of the condition in
children and adolescents
with DS
Auxology and
body
composition
Obesity Prevalence: 23-70% in childhood, 50% in adulthood
Weight gain and BMI should be assessed at
least yearly upon clinical
periodic evaluations
Dietary intervention, calories
management and physical exercise
should be promptly recommended in
case of progressive weight gain
People with DS show lower lean body mass
and an excess of visceral fat compared to
age-, gender- and BMI-matched
healthy controls
Short stature
The height of 75-90% of adults with DS falls below the
3
rd
centile with reference to the general population
growth charts
Height attainment in children and
adolescents with DS should be assessed by
syndrome-specific growth charts
Recombinant human growth hormone
is not routinely recommended in
individuals with DS
Average final height in subjects with DS is
153 cm in males and 143 cm in females
Glucose
metabolism
Type 1
diabetes mellitus Prevalence: 1.4-10.6%
- Caregivers should be periodically
informed about signs and symptoms
potentially consistent with hyperglycemia,
in order to prompt timely diagnosis and
treatment
- Fasting blood glucose and HbA1c levels
should be assessed whenever the clinical
suspicion of type 1 diabetes mellitus
is raised
Insulin
- Children and adolescents with intellectual
disability, as in DS, particularly benefit from
the introduction of sensors for continuous
glucose monitoring instead of self-
monitoring blood glucose by fingerstick
- Treatment-wise, recent technologic
advances play a pivotal role in achieving a
satisfactory glycemic control in patients with
intellectual disability and in preventing them
from experiencing severe or frequent
episodes of hypoglycemia
Type 2
diabetes mellitus Prevalence: 3.6%
- Fasting blood glucose and HbA1c levels
should be assessed in all children with DS
aged 10 years or more with age- and
gender-matched BMI above the 85
th
centile
or presenting specific risk factors (maternal
history of gestational diabetes, family
history of T2DM, high-risk ethnicities, signs
of insulin resistance)
- Among non-obese asymptomatic
individuals with DS, screening for T2DM
(fasting glucose and HbA1c levels) should
be assessed at the age of 30 years and every
three years thereafter
Oral antidiabetic medications or insulin
administration based on metabolic
control, as per international guidelines
for otherwise healthy patients
Children and adolescents with intellectual
disability, as in DS, particularly benefit from
the introduction of sensors for continuous
glucose monitoring instead of self-
monitoring blood glucose by fingerstick
Bone
metabolism
Reduced bone
mineral density
From 13% in adolescence and young adulthood, to
66% in elderly individuals.
Systematic screening by DEXA scan is not
recommended in pediatrics.
CAYA with DS who experience fractures
should undergo a biochemical evaluation to
rule out potential underlying causes
(hyperthyroidism, celiac disease, vitamin D
deficiency, hyperparathyroidism, the use of
detrimental medications) and a DEXA scan
The potential benefits of
bisphosphonates in treating low bone
mineral density in subjects with DS is
still debated
Diminished osteoblastic activity and
inadequate bone mass accrual, rather than
abnormalities in bone resorption, are
responsible for the low bone mass observed
in individuals with DS. Accordingly, the
potential efficacy of antiresorptive therapies
is debated
CAYA, children, adolescents and young adults; DS, Down syndrome; TFT, thyroid function tests; TPO, thyroid peroxidase; TG, thyroglobulin; BMI, body mass index; LH, luteinizing hormone; FSH, follicle stimulating hormone; T2DM, Type 2 diabetes mellitus; TSH,
thyroid stimulating hormone; DEXA, Dual energy X-ray absorptiometry.
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According to European Reference Network recommendations
for the management of CH, treatment must be started as soon as
possible, before the age of 14 days of life, with an initial dosage of L-
thyroxine of 10-15 µg/kg/day. Higher doses (15 µg/kg/day) are
indicated in severe cases (fT4<5pmol/L) and lower doses (10 µg/kg/
day) in milder cases (19).
Given the high prevalence of CH in DS, in case of a normal
neonatal screening, frequent monitoring throughout the first year of
life is recommended. The American Academy of Pediatrics (AAP)
recommends evaluation of thyroid function at least three times
during the first months (at birth, 6 and 12 months), and annually
afterwards (20). Most recently, the European Reference Network
guidelines for the management of CH in infants with DS
recommend one additional evaluation at 1 month of life (birth-1-
6-12 months and then annually) (19). Other Authors, such as Pierce
et al., endorse thyroid function control at 6-8 weeks of life and at 4
months (21). These additional screening timepoints are
recommended due to the high occurrence of neonatal
comorbidities in DS. Indeed, affected newborns experience a high
prevalence of non-thyroidal illness as a consequence of cardiac or
intestinal disease. Accordingly, TSH generation may be impaired,
resulting in a false-negative neonatal screening. Additional
measurement of TSH and fT4 in the first weeks/months of life
may prompt the timely detection of undiagnosed CH in this
selected sub-cohort of patients.
2.2 Autoimmune hypothyroidism
The incidence of Hashimoto thyroiditis is higher in individuals
with DS compared to the general population (10,22). In this setting,
anti-thyroid peroxidase (TPO) antibodies show a better positive
predictive value compared to anti-TG, especially in terms of
unfavorable evolution from subclinical hypothyroidism/
euthyroidism to overt gland hypofunction (23,24).
The gene AIRE, autoimmune regulator, is located on
chromosome 21 and codifies for a master controller of immune
tolerance, regulating the expression of tissue-specific antigens in the
thymus and T-cells selection. Its function, as well as that of other
genes, is reduced in individuals with DS due to the trisomic
imbalance, and is associated to thymic hypofunction, resulting in
a higher incidence of autoimmune disorders (25,26). Such
pathogenesis explains the lack of gender polarization among
patients with DS and autoimmune thyroid disorders, in contrast
with the remarkable prevalence in females within the general
population, for whom hormonal factors play a pivotal role.
Hypothyroidism in children with DS occurs at an earlier age
compared to healthy peers, but such finding may be the result of
systematic screening programs, leading to more frequent testing
among asymptomatic subjects (5,12). Diagnosis of Hashimoto
thyroiditis more frequently precedes or follows the onset of extra-
thyroid autoimmune diseases, such as alopecia (prevalence 6-10%),
celiac disease (5-10%) or diabetes mellitus type 1 (3 times more
frequent than in the general population) (5,11).
Diagnosis is more often made by routine blood testing, rather
than by clinical findings, as hypothyroidism in children with DS is
less symptomatic or presents with a specific signs such as hypotonia
and weight gain, which are common in people with trisomy 21
regardless of thyroid function (12,27–29).
Patients with Hashimoto thyroiditis and overt hypothyroidism
(low FT4 and compensatory increased of TSH) are candidate to
replacement therapy with L-thyroxine. Conversely, replacement
therapy is not recommended in asymptomatic patients with
normal thyroid function tests, though a systematic follow-up
should be undertaken in order to timely detect eventual
progression into hypothyroidism. Finally, several factors should
considered in the decisional process that eventually leads to
prescribe L-thyroxine in patients with subclinical hypothyroidism,
such as TSH values, reported symptoms and the clinical or
sonographic finding of goiter (10,30).
FIGURE 1
Occurrence of endocrine disorders among children and adolescents with Down syndrome (DS). Single disorders are grouped with reference to the
organ involved. Whenever literature reports different prevalence for the same disorder the median value was represented by the height of the bar,
while the range was represented by the vertical line connecting the lowest and the greatest occurrence.
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Levothyroxine dosage is titrated, until biochemical
euthyroidism is achieved. Though an average dosage of 1-2 mcg/
kg/day is usually sufficient in the general population, daily doses
ranging from 0.3 to 6.6 mcg/kg have been reported in children and
adolescents with DS (31). The first evaluation of efficacy by
assessing thyroid function tests is indicated not earlier than 6 to 8
weeks following treatment prescription and then every six
months (32).
2.3 Autoimmune hyperthyroidism
Graves’Disease shows prevalence rates as high as 0.66% in
children and adolescents with DS, thirty folds greater than in the
general population (33). As for Hashimoto disease, the pivotal role
of genetics on the pathogenesis of thyroid disorders results in an
earlier disease onset and lack of gender polarization among children
with DS (33).
In contrast with autoimmune hypothyroidism, hyperthyroidism
more frequently determines an acute presentation with classical
symptoms (palpitations, anxiety, heat intolerance, fatigue, tremors,
increased appetite, weight loss) and signs (hyperactivity, tachycardia,
arrhythmia, systolic hypertension, diaphoresis, hyperreflexia,
muscle weakness). Accordingly, diagnosis is more frequently
clinically-guided, rather than performed by routine laboratory
testing (33,34). Even so, the intellectual disability and subsequent
difficulty in reporting symptoms experienced by patients with
trisomy 21 may result in diagnostic delay in comparison to the
general population.
Anti-TSH receptor antibodies and thyroid ultrasound should be
sought whenever TSH is suppressed, either in the setting of a
symptomatic patient or in case of occasional finding upon
yearly monitoring.
There are three mainstay treatments: anti-thyroid medications
such as methimazole, thyroidectomy and radioiodine therapy (33).
As for the general population, pharmacological treatment is the
first therapeutic choice (35). Historically, several authors suggested
that surgery should be considered in case of failure of remission
after 2 years of treatment. Nevertheless, more recently, a growing
body of literature has shed light on the beneficial effects of
prolonged methimazole administration, if tolerated, at the
minimum maintenance dosage before attempting treatment
discontinuation, particularly in children (36–38).
Graves’disease seems to have a more favorable course in
individuals with DS compared to the general population. Indeed, the
reported percentages of relapse following a first course of anti-thyroid
medication are lower than in healthy controls (39). In addition, patients
with DS show greater percentages of persistent remission over time and
average lower doses of methimazole are generally needed to achieve
biochemical euthyroidism in comparison to the general population (39,
40). Nevertheless, some Authors have challenged these results, thus
supporting the hypothesis of a remarkable inter-individual variability
in response, remission rates and dosages required (33).
Thyroidectomy represents second line treatment in otherwise
healthy patients. Nevertheless, in children with Down syndrome,
anatomic factors such as short neck and airway malacia, along with
generalized hypotonia, result in a remarkable increase of
anesthesiologic risk class, thus leading clinicians to provide
indication to neck surgery only in case of demonstrated and
unequivocal failure of medical approach.
Finally, radiohyodine administration results in gland function
suppression, that prompts the need for a lifetime replacement
therapy with levothyroxine (33). Importantly, exposure to
radiation represents an independent risk factor for onset of
hematologic malignancies (41) and it is therefore regarded as
potentially harmful for subjects with DS, who are genetically
predisposed to develop lymphoblastic and myeloid leukemias per se.
2.4 Subclinical and overt non
autoimmune hypothyroidism
Subclinical non autoimmune hypothyroidism (SNAH) is
defined as the finding of an isolated increase in TSH with normal
free circulating thyroid hormones, in the absence of autoimmune
disease, goiter or clinical symptoms.
The reported prevalence rates in people with DS is as high as 10-
39% (12,21,42–44), thus resulting as the most frequent thyroid
dysfunction in this population. In addition, it is likely that the real-
life occurrence of SNAH is probably underestimated because of the
asymptomatic nature of the disorder (31). Most of the remarkable
variability in the prevalence range reported by different studies
depends on the poor consensus about the gender- and age-specific
reference ranges of TSH values in individuals with DS.
We recently assessed thyroid function tests over time among
550 pediatric children and adolescents with DS and outlined DS-
specific reference ranges and nomograms for thyroid function
parameters. Our data show a life-long upward shift of TSH
compared to healthy age- and gender-matched peers (45). It has
been hypothesized that the additional chromosome 21 may affect
the regulation of hypothalamic-pituitary-thyroid axis, thus resulting
in slightly increased average TSH levels compared to
healthy controls.
The pathogenesis of subclinical hypothyroidism in subjects with
DS may be multifactorial. Several determinants have been
hypothesized by different authors as potentially involved in the
pathogenesis of SNAH, such as delay of maturation of the
hypothalamus-hypophysis-thyroid axis, inappropriate central
secretion of TSH, lower biological activity of TSH, lower
sensibility of TSH-receptor, inadequate dopaminergic down-
regulation of TSH secretion and over-expression of genes located
on chromosome (34,46).
From a prognostic perspective, factors predicting the evolution
of subclinical hypothyroidism into overt pictures are poorly
reproducible. Thyroid function tests show a remarkable intra-
individual variability over time, as proven in longitudinal long-
term assessments (45). Accordingly, several authors have
demonstrated that SNAH shows a transitory course in more than
70% of cases (29,46), especially when TSH values are just above the
upper reference limit (17).
Indications for starting thyroid hormonal replacement therapy
in individuals with DS and SNAH are object of debate; to date,
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conflicting positions lead to a lack of consensus. The aim of
levothyroxine would be to normalize TSH values, determining an
improvement in developmental and cognitive performances. Van
Trotsenburg et al. found a slight motor delay in 2-year-old infants
with DS and subclinical hypothyroidism who were not treated in
comparison to treated controls (19). Such difference was not
observed over a ten-year long follow-up (47). Some studies
revealed benefits of replacement therapy and normalization of
TSH values in terms of growth velocity, height, and head
circumference (17,47,48); no improvement of motor and
cognitive development was found (47). Besides, most of these
results have been systematically challenged by different authors,
who did not confirm such findings (31).
In conclusion, efficacy of treatment has not been proved and
there is no consensus on cut-off values for starting substitutive
therapy. Nevertheless, most guidelines agree on treating patients
with TSH values above 10mU/ml, goiter, or overt symptoms (10,
49). Before starting any treatment, thyroid function must be re-
evaluated, given the remarkable interindividual variability (45).
2.5 Thyroid disorders: from adolescence
to adulthood
In adults with DS, thyroid disorders represent the most
common chronic comorbidities. The reported prevalence of
hypothyroidism in this population ranges from 39% between 18
and 29 years to 51% in individuals aged 30 or older (50,51).
Only few studies on the long-term evolution of thyroid function
in adults have been published. In detail, conflicting outcomes have
been reported regarding the advantage of treating elevated
thyrotropin levels in asymptomatic patients, the diagnostic
accuracy of antithyroid antibodies and the clinical utility of
routinely assessing anti-thyroid antibodies to screen for thyroid
disease in adults with DS (52).
Prasher and colleagues have demonstrated, through a long-term
follow-up, that most individuals with DS develop thyroid disorders
in childhood and adolescence, while over 73% of young adults
without thyroid dysfunctions persistently show normal thyroid
function tests as they grow older. In addition, most adult subjects
with subclinical hypothyroidism are not expected to develop overt
hypothyroidism (53).
Thus, infancy, adolescence and young adulthood are key phases
for the overall life-long risk of developing dysthyroidism in DS.
Nevertheless, also the guidelines for the management of adult
patients with DS recommend regular screening for thyroid
function tests every 1-2 years (52).
3 Puberty and gonadal function
While there have been numerous reports on gonadal
dysfunction in individuals with DS, research on pubertal
attainment and sexual development in this population is scarce
and mostly limited to historical studies (54,55). In addition, overall
outcomes have been conflicting, with some studies reporting an
increased incidence of gonadal dysfunction (54), while others
demonstrating an intact pituitary-gonadal axis and retained levels
of circulating sex hormones (55–57).
Concerning pubertal timing, historical analyses have outlined
that the average onset puberty was set around 13 and 12 years in
male and female people with DS, respectively (54,57). These data
apparently differ from those drawn by more recent studies. For
example, in a cohort of children with DS, Erdogan and colleagues
reported pubertal onset at a median age of 10.0 years for both
genders, which is superimposable with the outcomes more recently
described for age-matched peers (58). In addition, the average age of
menarche in adolescents with DS is consistent with the general
population in several study cohorts (58–60). Overall, the difference
in the timing of pubertal attainment reported by different authors
likely mirrors most of the changes experienced by the general
pediatric population over the last decades. Indeed, the tempo of
pubertal onset and progression is influenced by multiple factors,
including nutrition, genetics and the environment. Over the past
century, the average timing of pubertal development has decreased
by approximately 0.3 years every 10 years in the general population
(61). This phenomenon has been attributed to improved nutrition
and higher socioeconomic status among children and involves both
otherwise healthy and syndromic people.
Due to the scarcity of data concerning gonadal function in
pediatric subjects with DS, it is currently not possible to provide
detailed information about the incidence of hypogonadism.
The most extensive studies on gonadal function held in DS have
focused on male, post-pubertal individuals. Indeed, few analyses
have assessed luteinizing hormone (LH), follicle-stimulating
hormone (FSH), and testosterone levels among subjects with DS,
aiming at reporting the prevalence of hypogonadism in this
population (54,56). Approximately 70% of the individuals
enrolled displayed elevated FSH and LH levels compared to the
median values observed in post-pubescent controls, while
testosterone levels were found to be superimposable with the
average values recorded in otherwise healthy adult males (56–58).
Based on these biochemical criteria, a non-unremarkable share of
people with DS could be classified as presenting “compensated
hypogonadism”(high LH levels in the setting of normal total
testosterone levels). These data support the hypothesis of a
certain degree of Leydig cell impairment in DS and has also been
described in early infancy. It could be inferred that this condition is
most likely congenital in nature and, consistently, strictly related to
trisomy itself (62).
The increase in serum FSH levels after puberty has been
regarded as an indication of germ cell dysfunction, as reported in
previous studies (54,56). Accordingly, although three cases of
spontaneous conception have been described (63–65), male
individuals with DS are known for presenting with a significantly
impaired fertility. On the one hand, this could be the mere result
of the relatively small proportion of sexually active individuals
with DS aiming at procreating. On the other hand, impaired
spermatogenesis along with dysfunction in Sertoli cells among
men with DS is likely to play a pivotal role (54,61,62). These
hypothesis is also consistent with the average testicular volume
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recorded in subjects with DS, remarkably lower than those recorded
in age-matched healthy controls (54,61).
Conflicting data have been published concerning gonadal
function among women with DS. Though no systematical
association with primary ovarian insufficiency has been published,
in some studies FSH levels were found to be abnormally high (54,
56). Conversely, Angelopoulou and colleagues described levels of
gonadotropins within normal range (60). However, the average LH
levels were significantly greater that those assessed in controls,
consistently with the findings reported by other authors (54,56).
Overall, women with DS have been shown to be potentially
fertile, as highlighted by several reported cases of maternity (66–70).
Nevertheless, in a post-mortem autoptic study conducted on girls
with DS, ovaries were found to show either a lack of follicle
maturation or delayed follicle development. Additionally, there
were differences in the number and size of antral follicles, as well
as an early decline in small follicles, particularly noticeable after the
third year of life (71). These features remarkably diverged from the
findings collected in otherwise healthy controls, who exhibited
distinct patterns of follicle growth and development (71).
Consistently, from a biochemical perspective, women with DS
experience an early and significant decrease in anti-Müllerian
hormone (AMH) levels, universally regarded as a marker of
ovarian reserve and strictly related to the overall pool of ovarian
antral-phase follicles (72). As a consequence, woman with DS tend
to experience menopause at a marginally younger age compared to
the general population (71–73), with a reported median age of
46 years.
4 Auxology
In children with DS, it is recommended that weight and height
trends are monitored and plotted on syndrome-specific charts (74).
Indeed, length/height, head circumference and growth velocity are
lower from birth onwards, compared to age- and gender-matched
non-trisomic peers.
4.1 Growth
Short stature is one of the main auxological features of Down
Syndrome. The reported average adult height is 153 cm in males
and 143 cm in females (75). Short stature is mostly due to reduced
length of limbs, while the trunk commonly shows a retained size
(75). Overall, sitting height-to-height ratio is greater compared to
the general pediatric population.
The etiology of short stature in DS has not yet been completely
clarified. Recent studies have reported a certain degree of
impairment of the GHRH-GH-IGF1 axis in subjects with trisomy
21. In detail, some authors have highlighted that short stature in DS
can result from a combination of unsatisfactory hypothalamus–
pituitary secretion and reduced bioactivity of endogenous GH (76).
The prescription of recombinant human growth hormone
(rhGH) in this population has been historically widely debated,
due to ethical considerations on the benefits provided in terms of
gain of height and due to conflicting results on its efficacy. The
recurrent lack of controls, the limited follow-up, as well as the
heterogeneous outcomes among treated patients has led to poorly
reproducible conclusions (77). A recent meta-analysis reports a
short-term efficacy of rhGH treatment on the growth of children
with DS, irrespectively of endogenous GH secretion patterns (76).
Nevertheless, most studies did not manage to demonstrate a longer-
lasting and durable positive effect of the treatment on growth
attainment (78–80). In addition, long-term analyses are lacking
and systematic data about rhGH safety in a population exposed to a
greater occurrence of malignant hematological disorders are not
available. Accordingly, though DS patients should not be precluded
from GH therapy per se, no clear indication can be provided and
rhGH is often proscribed to date. Benefits and disadvantages should
be discussed with the parents and child and the approach should be
patient-tailored (76).
4.2 Body composition
With regard to body composition, infants present with poor
weight gain from birth to infancy, mostly because of feeding-related
issues due to hypotonia and macroglossia or associated
comorbidities, including heart defects and gastrointestinal
malformations (81). This trend tends to reverse from late
childhood to adolescence, with reported obesity rates as high as
23-70% (82–85). Obesity can complicate conditions such as
obstructive sleep apnea, diabetes and cardiovascular disease (86).
The cause of the increased occurrence of obesity and overweight
must be sought in slow basal metabolism, low circulating leptin
levels, hypotonia, susceptibility to systemic inflammation and
possibly concomitant hypothyroidism (81,83,87,88). In
addition, impaired mobility and motor clumsiness may negatively
affect physical activity and thus result in an overall sedentary
lifestyle. Furthermore, several studies have connected the
shortening of the telomeres, which causes accelerated aging in
DS, with the increase of body mass index (BMI) and adiposity (89).
It is important that families are periodically advised about
healthy diet programs and exercise promotion in order to prevent
obesity (86). Pediatric endocrinologists and pediatricians play a
pivotal role in preventing children and adolescents from gaining
excessive weight and becoming obese adults. Indeed, obesity
remains a leading clinical issue among adults with DS, with
reported prevalence rates as high as 50%. Accordingly, a life-long
follow-up with yearly weight and BMI check is strictly
recommended among adults with DS. Dietary intervention,
calories management and physical exercise are the main
therapeutic measures, with the aim of reducing obesity-related
comorbidities (86). Bariatric surgery is controversial in adults
with intellectual disability (88).
5 Glucose metabolism
Though the scientific community has historically focused on the
clinical and epidemiological burden of type 1 diabetes mellitus
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among children with DS, a growing body of literature has shed light
upon the greater occurrence rates of type 2 diabetes compared to the
general population (90).
5.1 Type 1 diabetes mellitus
The remarkable increase in the risk of developing autoimmune
disorders experienced by individuals with DS (40,91) is overt
when looking at the four-fold greater prevalence of type 1
diabetes mellitus (T1DM) compared to the general pediatric
population (90).
The first epidemiological report of this clinically significant
association dates back to 1968, when Milunsky and colleagues firstly
highlighted the occurrence of diabetes (either insulin-dependent or
-independent) in a wide population of over 20.000 individuals
diagnosed with trisomy 21 (92).
The median age at diagnosis shows a biphasic distribution, with
afirst peak before the age of 2 years and the second in early
adolescence (10 years) (93). The median age for the onset of T1DM
in children with DS is 8 years, about 6 years earlier than in the
general pediatric population (94). Both genders show
superimposable incidence rates (91).
The specificities of the epidemiology of T1DM in subjects with
DS is strictly related to the abovementioned predisposition to
develop dysimmune phenomena related to the over-expression of
genes located on trisomic chromosome 21. Accordingly, children
with DS experience an increased co-occurrence of type 1 diabetes
and different autoimmune disorders, such as Hashimoto thyroiditis
(74%), coeliac disease (14%) or both (8%), as reported by Aitken
and colleagues (95).
Several genomic analyses have reported an excess of diabetes-
associated HLA class II genotypes in children with both DS and
T1DM compared to healthy controls (95). Nevertheless, DS
children with T1DM are less likely to carry the highest- risk
genotypes (i.e. DR4-DQ8/DR3-DQ2), as they are more prone to
carry low-risk ones (95–97). Accordingly, it has been speculated
that additional factors, possibly involving genes located on
chromosome 21, may increase the penetrance of T1DM in
children with DS. For example, the co-occurrence of increased
copies and point mutations on both AIRE gene (21q22.3) and its
promoter, may lead to the overexpression of its transcript, which
regulates T-cell function and self-recognition, thus contributing to
the secretion of anti-pancreatic islets autoantibodies (98).
Consistently, recent analyses have demonstrated a certain
degree of chronic flogosis and over-expression of pro-
inflammatory cytokines among individuals with DS, as a result of
the constitutional dysregulation of IL-6 signaling pathway (99).
This unfavorable biological milieu is known to promote
autoimmune phenomena, with subsequent overproduction of
autoreactive antibodies. All these features may contribute to the
development of a breach into immune tolerance.
The clinical signs and symptoms of diabetes in children with DS
are similar to those reported in the general pediatric population, but
the younger age upon diagnosis in combination with the cognitive
and language impairment related to the syndrome may result in a
diagnostic delay (100,101).
Despite the cited constitutional dysregulation of immune
system, children with DS affected by T1DM seem to show an
overall better metabolic control, requiring lower insulin daily
dose, in comparison to age-matched peers from general
population (96). Accordingly, patients with DS present a lower
prevalence of diabetic complications (such as retinopathy,
nephropathy and neuropathy). A potential explanatory hypothesis
is that patients with DS often adopt a more systematic lifestyle and
display an overall better compliance to routine treatment than
otherwise healthy peers (102).
5.2 Type 2 diabetes mellitus
Concerning type 2 diabetes mellitus (T2DM), prevalence rates
as high as 3.6% have been reported in children and adolescents with
DS (103). As for the adult general population, higher body mass
index (BMI), family history consistent with impaired glucose
metabolism and female gender are all potentially detrimental
factors playing a negative role upon insulin-sensitivity (96).
A recent study reported a 10-fold increase in the incidence of
T2DM among individuals with DS aged 5 to 14 years compared to
age- and gender-matched peers, while occurrence rates were only
doubled over the age of 54 years (104).
This increased incidence is likely to be related to predisposition
to peripheral insulin resistance and declining b-cell function as a
consequence of obesity and reduced physical activity (105). Indeed,
though fat mass index, percentage of body fat, and lean BMI are
superimposable in adolescents with and without DS, syndromic
individuals show lower lean body mass for a given BMI Z score
compared to general population. In addition, visceral fat represents
a greater share of the body fat mass recorded in subjects with DS
(106). Overall, a less favorable body composition leads to greater
occurrence rates of insulin resistance among trisomic patients.
5.3 The screening of glucose metabolism
As debated above, children and adolescents with DS show an
increased risk of developing either type 1 or type 2 diabetes. Though
no univocal guidelines about screening and treatment of impaired
glucose metabolism in the pediatric population with Down
syndrome have been published to date, several consortia have
provided dedicated recommendations.
Timely detection and treatment of diabetes mellitus are crucial
in this at-risk population. National and international consortia for
the care of children and adolescents with intellectual disability
recommend systematic assessment of signs and symptoms
potentially consistent with hyperglycemia and prompt dedicated
testing in case of clinical suspicion, given the 5-fold increase in the
risk of developing DM recorded among patients with variable
degrees of intellectual disability (100,101). In addition, adequate
information about signs and symptoms of T1DM should be
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provided to the caregivers of children with DS, in order to promote
prompt diagnosis and early treatment (107). Despite a greater
occurrence of T1- and T2DM in this selected cohort, there is
poor agreement about the best screening approach to monitor
glycemic metabolism. The AAP guidelines for the management of
children and adolescents with DS do not recommend periodical
systematical assessment of either blood glucose or glycated
hemoglobin (HbA1c) levels among asymptomatic subjects (20).
Consistently, the guidelines for the care of adults with DS advocate
that screening for DM is started from the age of 30 years onwards
and every 3 years thereafter (52). On the other hand, a growing
body of independent charities focused on the care of children with
DS has started to promote annual screening of fasting blood glucose
levels and HbA1c from the age of 14 onwards (108).
Overall, clinicians should also remember to apply the
recommendations provided by the American Diabetes Association
(ADA) for otherwise healthy pediatric subjects. Indeed, screening
for prediabetes and for T2DM is warranted in all asymptomatic
children and adolescents aged 10 years or older with age- and
gender-matched BMI above 85
th
percentile or with at least one of
the following risk for diabetes: maternal history of gestational
diabetes and/or family history of T2DM among first or second
degree relatives; or high-risk ethnicities (Native American, African
American, Latino, Asian American, Pacific Islander); or signs of
insulin resistance; or additional disorders associated with insulin
resistance (109). The screening should be performed both with
fasting glucose plasma level and HbA1c levels, every three years or
more in case of rapidly increasing BMI. Oral glucose tolerance test
should be prescribed for a more accurate evaluation of dysglycemia,
such as when the clinical suspicion for diabetes or impaired glucose
tolerance remains high despite non-diagnostic blood glucose or
HbA1c levels (109). Similar recommendations can be drawn also for
adult subjects with DS. Indeed, the ADA recommends that
individuals showing a BMI of 25 or greater and at least one
additional risk factor should undergo screening for type 2
diabetes every 3 years after achieving puberty (109). As DS can be
regarded as an independent risk factor for T2DM, a dedicated
biochemical screening should be undertaken in any overweight
adult with DS, regardless of the presence of additional
comorbidities (52).
Interestingly, children with DS tend to present with higher
fasting glucose levels than otherwise healthy peers, but
unexpectedly lower HbA1c levels (106). The reason for decreased
HbA1c levels among participants with DS still needs to be clarified.
Wachtel and Pueschel reported macrocytosis in individuals with DS
as well as increased red blood cell turnover (110). If the latter is
confirmed, a shortened red blood cell life span could lead to a
factitious decrease in HbA1c levels.
5.4 Monitoring and treatment of
diabetes mellitus
Children with T1DM and their families are generally
encouraged to check blood glucose levels about four times a day,
in order to customize insulin treatment and to avoid events of
hyper- or hypoglycemia. In addition, these data provide healthcare
professionals with an adequate amount of data to adapt insulin
posology upon periodical evaluations.
In the last decades, the scientific Community has witnessed a
dramatic improvement in the technological achievements for the
monitoring of blood glucose levels among diabetic patients (111).
Children and adolescents with intellectual disability, as in DS,
particularly benefit from the introduction of sensors for
continuous glucose monitoring (CGM) instead of self-monitoring
blood glucose by fingerstick. Real-time CGM systems perform a
systematic and continuous assessment of patient’s interstitial
glucose levels over time. This technology is effective in providing
the user with prompt information about current glucose reading, at
any time of day. In addition, CGM devices generate patterns of
glucose trends that can be analyzed retrospectively to clarify the
overall glycemic balance, playing a pivotal role on potential patient-
tailored therapeutic decisions. In addition, alarmed systems for the
early detection of hypoglycemic episodes have remarkably
improved the quality of life and reduced adverse events in this
population of patients, that may be less aware of the signs and
symptoms consistent with low blood glucose levels or less prompt in
informing the caregiver about incipient severe hypoglycemia (112).
Treatment-wise, the technological innovations in insulin
therapy (such as smart insulin pens and insulin pumps with
automatic insulin infusion) play a pivotal role, nowadays, in
achieving and maintaining satisfying glycemic control with a
lower risk of micro- or macroangiopathic complications, in
children with T1DM and DS.
Insulin pumps provide small amount of insulin and can be
programmed to vary on an hour-by-hour basis. They are especially
recommended in younger children and for those in whom
hypoglycemia cause remarkable management issues (113).
Prevention of type 2 diabetes requires multifactorial treatment
including lifestyle modification, regular physical exercise and body
weight control. Metformin has been historically regarded as a
mainstay in the treatment of T2DM in pediatrics. The use of
liraglutide, a GLP1 agonist, has been recently approved both for
weight reduction and for diabetes, also in the pediatric population.
Obviously, insulin therapy is the first therapeutic choice in case of
severe glycemic decompensation at the onset (111).
6 Bone health
The progressively increasing life expectancy in individuals with
DS has shed light on the occurrence of osteopenia, osteoporosis and
fractures, overall greater than the one recorded in the general
population (114). Indeed, among adults with DS, about one out
of four is affected by osteoporosis (115) and median bone mineral
density (BMD) values recorded in this population are lower than in
age- and gender-matched controls, irrespectively of the degree of
intellectual disabilities (ID) (116,117). Longitudinal studies have
indicated that bone mineral density (BMD) decreases at a faster rate
with age in individuals with DS compared to the general population
(50), exposing adults with DS at an increased risk of developing
osteoporosis and experiencing bone fractures (115). As DS is
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regarded as a progeroid syndrome (118), i.e. adults with DS present
healthy issues common in elderly people, it could be hypothesized
that the greater incidence of low BMD is the expression of an earlier
occurrence of a disorder typical of aging (50). In addition, as
previously discussed, the early onset of menopause in women
with DS may play an additional detrimental role on bone health
(115). Consistently, the evidence of a lower BMD has been found
even in children and adolescent with DS, compared with healthy
peers (119–121).
Dual-energy X-ray absorptiometry (DXA) is the gold standard
to screen bone health, but people with DS are less likely to receive
BMD testing, for several reasons including intellectual disability,
that makes the procedure less affordable (115).
Additionally, DXA-derived BMD does not take into account the
differences in bone size between DS and otherwise healthy controls,
potentially overestimating osteopenia (116). Accordingly,
volumetric BMD (vBMD or bone mineral apparent density
(BMAD)) estimated on the three-dimensional parameter, should
be preferred as it better reflects the skeletal assessment in subjects
with DS, overcoming the problem of morphological differences
(116). Moreover, adjusting BMD for body height, weight and total
lean mass is even more important in children, in order to take into
account their physical modifications due to growth (122). For these
reasons, to date, only few studies on adjusted BMD have been
conducted within the pediatric population with DS.
In a cornerstone study conducted by Carfiand colleagues, DXA
was used to assess BMD at the femoral neck and lumbar spine in
234 adults with DS compared to 2206 adults from the general
population, enrolled in the National Health and Nutrition
Examination Survey dataset. The results revealed significantly
lower mean BMD and BMAD in the DS group compared to
controls. These findings also highlighted a strong association
between these measurements and age, especially in the DS group.
In this study, average BMAD levels of adults with DS aged 40–49
was superimposable to that of controls aged 60–69, suggesting the
importance of initiating early screening for osteoporosis in adults
with DS (50).
Interestingly, despite the reported universal agreement about
the overall reduced median BMD among adults and young adults
with DS (57,60,116,120), conflicting opinions have been reported
about bone density in children, mainly due to divergent
methodologies, analyses, and sample features among published
studies (116,119,121,123). In detail, Wu and colleagues reported
lower BMD and bone mineral content (BMC) exclusively in the
pelvic region of 7-to-10 years-boys (123). Combining these results
with those by Gonzalez-Agüero and colleagues (119) and Baptista
et al. (116), it can be speculated that in DS reduced BMD does not
occur before adolescence and that the pelvis shows the earliest
involvement (123). Concerning fractures, data drawn from the DS-
Connect questionnaire showed that the occurrence of fractures in
the enrolled population was as high as 27%, mostly involving
younger age classes (124).
Concerning sex-driven prevalence, in contrast to the higher
prevalence of osteoporosis and osteopenia in men with DS
compared to women (121), female children and adolescents with
DS are described to have a lower bone mass peak than age-matched
trisomic males (122).
Data about bone turnover markers in the pediatric population
with DS are lacking. In adults with DS, McKelvey and colleagues
demonstrated that both women and men with trisomy 21, without
consistent clinical risk factors for osteoporosis, showed lower levels
of bone deposition markers compared to individuals without DS
(125). This profile is significantly associated with low BMD,
regardless of gender. These findings suggest that diminished
osteoblastic bone formation and inadequate bone mass accrual
are the main responsible for the low bone mass observed in
individuals with DS. This contrasts with postmenopausal or senile
osteoporosis, in which increased bone resorption is regarded as the
primary pathogenic factor. These observations, confirmed also by
more recent analyses (126,127), raise doubts about the effectiveness
of antiresorptive therapies in this specific population.
The etiology of osteoporosis in DS is multifactorial. The genetic
imbalance due to trisomy 21 has been described as a main
determinant of low bone mineral density in individuals with DS
(114). Blazek et al. reported that transgenic Ts65Dn mice, owing 3
copies of about half of the genes of human chromosome 21, showed
craniofacial and appendicular skeletal phenotype resembling the
one observed in humans with DS (128). Subsequently, the same
Authors described that the overexpression of DYRK1A gene
induces skeletal abnormalities and abnormal bone homeostasis,
especially in transgenic male mice, while a normal copy number of
DYRK1A results in a normal development of the appendicular
skeleton and bone turnover (129). In addition, utilizing a mouse
mapping panel, it has been demonstrated that additional triplicated
orthologous genes located on chromosome 21 may play a role in
determining an abnormal skeletal phenotype (130). Also epigenetic
modifications, e.g. overexpression of the receptor interacting
protein 140 (RIP140) have been related to poorer bone health
and may play a role in low BMD of people with DS (131,132).
Besides genetics, several potential environmental risk factors for
low BMD are common among patients with disability, such as poor
dietary habits with scarce calcium and vitamin D intakes, limited
sun exposure, sedentary lifestyle and reduced physical activity
(120). Additionally, hypotonia and the frequent use of
anticonvulsants may contribute to bone depletion (133), as well
as the increased risk of developing coeliac disease and the
forementioned endocrine disorders (45,57,103).
Preventive strategies include adequate calcium and vitamin D
intake, appropriate sunlight exposure and the medical treatment of
endocrine comorbidities (134). Similarly, routine physical exercise
and active lifestyle are crucial to increase muscular strength and
bone mass peak, especially during adolescence (119,134–136).
Treatment options for osteoporosis in DS are currently limited
and further studies are needed. Indeed, bisphosphonates may not
provide benefits as they reduce bone turnover, instead of acting on
bone accrual, which is described to be the main issue in patients
with DS, as previously stated (125). Accordingly, Fowler and
colleagues reported that PTH intermittent treatment in Ts65Dn
mice significantly increased bone mass and volume suggesting that
anabolic treatments, as intermittent-PTH and anti-sclerostin
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antibodies (127), may be effective in improving BMD in subjects
with DS (136).
Finally, given the key role of genetics on bone health in DS, gene
therapy, e.g. targeting DYRK1A, and histone manipulation for
epigenetic modifications may be promising future solutions
(114,137).
7 Conclusions
In conclusion, DS is associated to a remarkable increase in the
risk of developing multiorgan comorbidities, including
endocrine disorders.
Thyroid disease represents a wide share among the endocrine
disorders recorded in children and adolescents with DS. Given the
remarkable occurrence of congenital and early-onset
hypothyroidism, a strict systematic monitoring of thyroid
function tests is warranted at birth and along the first year of life.
Subsequently, the risk of developing autoimmune thyroid disorders
prompts the universal indication of a lifelong screening program for
thyroid health among subjects with DS at any age.
Regarding gonadal function, the timing of onset and the
progression of pubertal attainment among individuals with DS
are superimposable to those recorded in the general population.
Nevertheless, in adult males compensated hypogonadism is a
frequent finding and fertility is often compromised. On the other
hand, women with DS display retained fertility, despite a slightly
premature menopause.
From an auxological perspective, short stature is the main
auxological outcome among individuals with DS. Though a
potential impairment in the GHRH-GH-IGF-I axis has been
hypothesized, the prescription of rhGH is still subject of debate, due
to controversial data about its efficacy and safety in children with DS.
In addition, patients with DS are exposed to a four- and ten-fold
increase in the risk of developing either type 1 or type 2 diabetes,
respectively. Overweight children and adolescents with DS deserve
a dedicated monitoring to timely detect and treat hyperglycemia.
Finally, young adults with DS tend to present a lower bone
mineral density compared with age-and sex-matched healthy
controls. Impaired osteoblast function and subsequent insufficient
bone peak mass accrual during adolescence and young adulthood
represent the key causative factors for low BMD in DS (120,125,127),
rather than increased bone resorption. Accordingly, the potential role
of antiresorptive agents is questionable in this population.
By adopting organ-specific health surveillance, from childhood
to adulthood, an all-embracing care can be provided to individuals
with DS and their families, addressing their specific needs and
improving life expectancy and quality of life.
Author contributions
SM: Conceptualization, Writing –original draft, Writing –review
& editing. CF: Conceptualization, Writing –review & editing. MN:
Writing –review & editing. SdM: Writing –original draft. MF:
Writing –original draft. FL: Writing –original draft. LO: Writing –
original draft. CP: Writing –original draft. ML: Writing –original
draft. AG: Writing –review & editing. AL: Writing –review & editing.
DS: Writing –review & editing. CV: Writing –review & editing. GC:
Writing –review & editing. CD: Writing –review & editing. ABi:
Writing –review & editing. ABa: Writing –review & editing. AC:
Conceptualization, Writing –original draft, Writing –review & editing.
Funding
The author(s) declare that no financial support was received for
the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
The author(s) declared that they were an editorial board
member of Frontiers, at the time of submission. This had no
impact on the peer review process and the final decision.
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