ISSN: 1138-011X

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SD
Volume 17Number 1

January-April

INTERNATIONAL
MEDICAL REVIEW ON
DOWNS SYNDROME

Contents

2013

Editorial
1

25th Anniversary of the Centre Mdic Down

Josep M. Corretger Rauet

Original articles
3

Physical exercise and urinary uric acid levels in Downs

syndrome
C. Campos Vaquero, R. Guzmn Martnez, E. Lpez-Fernndez
and A. Casado Moragn

Maternal age: a controversial factor in trisomy 21

M. Vashist and Neelkamal

Case report
13

Unusual cause of respiratory distress: Morgagni hernia

associated to Downs syndrome
S. Degerli, N. Dereli, S. Sahin and E. Ozayar

DS

INTERNATIONAL MEDICAL REVIEW

ON DOWNS SYNDROME

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SD

INTERNATIONAL
MEDICAL REVIEW ON
DOW'N SYNDROME

Editorial Committee




Editor: Josep M. Corretger

Editor-in-Chief: Agust Sers
Editorial and Coordination: Katy Trias Trueta

Cardiology: J. Casaldliga
Dermatology: J. Ferrando
Dietetics-nutrition: N. Egea
Endocrinology: A. Goday
Maxillofacial Surgery: A. Monner
Genetics: A. Sers
Geriatrics: C. Farriols
Gynaecology: J. Cararach
General Medicine: A. Garnacho
Child Neurology: A. Nascimento
Adult Neurology: S. Fernndez
Dentistry and Orthodontics: M. A. Mayoral
Child Ophthalmology: A. Galn
Adult Ophthalmology: J. Puig, S. Simn
Ear, Nose and Throat: J. Domnech
Paediatrics: J. M. Corretger, M. Hernndez
Psychology: B. Garva
Psychiatry: J. Barba
Traumatology and Orthopaedics: F. Torner

Medical Advisers
F. Ballesta Martnez
M. Cruz Hernndez
J. Moreno Hernando
S. M. Pueschel (USA)

Psycho-pedagogy advisers
FCSD Team
J. M. Jarque
T. Vil
L. Brown (USA)

Editorial Secretary
Mar Cabezas

21

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Rev Med Int Sindr Down. 2013;17(1):1-2

INTERNATIONAL
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EDITORIAL

25th Anniversary of the Centre Mdic Down

Josep M. Corretger Rauet
Paediatrician, Medical Director of Centre Mdic Down, Barcelona, Spain

It is 25 years since the Centre Mdic Down (CMD) opened its

doors under the auspices of the Fundaci Catalana Sndrome de Down (FCSD), which was formed 3 years earlier, in
1984. Its foundational aim was to implement a systematic
health program, with an emphasis on prevention, for people with Downs syndrome (DS), complementary to the neuromotor activities imparted to this population, from birth
to adulthood. The progressive development of its health
care, teaching and research works has led it to become a
unique entity with these characteristics.
Two events took place during November and December
2012 to help celebrate this anniversary.
The anniversary itself was celebrated on the 3rd of December with a distinguished academic event in the Ofcial
Medical College of Barcelona (COMB). The event consisted
of the wholehearted support of the Catalonian Health Authorities of the activities of the CMD. It was chaired by the

Hon. Mr Boi Ruiz, of the Catalonian Regional Government

Department of Health, and the Chairman of the COMB, Dr.
Vilardell, who very brilliantly, and with great knowledge of
its activities, summed up the experience and value of the
Centre. After a brief analysis of its progress during these 25
years, the latest proposal by the FCSD, the Downs Syndrome and Alzheimer Centre, was presented. Drs. Jordi
Cam, Director of the Pasqual Maragall Alzheimer Foundation, Juan Fortea, Neurology Specialist of the Memory Unit
of the Hospital de Sant Pau of Barcelona, and Sebasti Videla, Research Director of the CMD presented this proposal.
The aim of this new Unit is to contribute to the knowledge
of the aspects that the syndrome adopts in adults with DS,
who currently enjoy a longevity and quality of life unthinkable a few years ago. The research team consists of the
aforementioned Professors and Specialists in Neurology,
Neuropsychology, and Social Work of the CMD, with support

Presentation of the Downs Syndrome and Alzheimer Unit.

1138-011X/$ - see front matter 2012 Fundaci Catalana Sndrome de Down. Publicat per Elsevier Espaa, S.L. Tots els drets reservats.

01 EDITORIAL ingl (1-2).indd 1

11/04/13 13:08

Josep M. Corretger Rauet

by the rest of the staff of the Centre, particularly the Internal Medicine, Geriatrics, Clinical Psychology, and Dietetics
Departments.
A few weeks before this event, between the 15th and
22nd of November, an emotive meeting took place in Quito,
Ecuador, which led to closer links between the medical
group of the CMD and Ecuadorians closely involved in the
care of people with DS in their country. The main reason
was the presentation of the Ecuadorian edition of the book
Your child with Downs syndrome. From A to Z, published by
the FCSD itself in Barcelona in 2008. Paediatricians from
Catalonia and Ecuador, including Dr. Ernesto Quionez (who
hosted the meeting), have collaborated in its publication
since its rst edition. The presentation was incorporated
into a series of lectures on the particular functions of the
FCSD and its experience in the evolutionary aspects of neurodevelopment and sleep in children with DS, and were
given by this author and Dr. Mara Dolores de la Calzada,
Consultant Neurophysiologist of the FCSD. The lectures took
place in the Quito Hospital Metropolitano and in the El
Tringulo Foundation of the same city, and which is wholly
dedicated to the needs of children and adolescents with
Trisomy 21.
The work of this model Foundation goes beyond the use
care programs of this group, giving priority to teaching
aimed at achieving full integration, now and in the future,
in all levels of society. The cooperation between the families and the professionals of the Centre is exemplary, thus
helping to achieve the proposed aims of improving the development of the abilities in people with DS and in their
contribution to enriching society as a whole.

Ecuadorean issue of the book Su hijo con sndrome de Down.

De la A a la Z.

01 EDITORIAL ingl (1-2).indd 2

11/04/13 13:08

Rev Med Int Sindr Down. 2013;17(1):3-7

INTERNATIONAL
MEDICAL REVIEW
ON DOWNS SYNDROME

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www.elsevier.es/sd

ORIGINAL ARTICLE

Physical exercise and urinary uric acid levels in Downs syndromea

C. Campos Vaquero, R. Guzmn Martnez, E. Lpez-Fernndez and A. Casado Moragn*
Department of Cell and Molecular Medicine, Spanish National Research Council Biological Research Centre (CSIC),
Madrid, Spain
Received on September 29, 2012; accepted on December 21, 2012

KEYWORDS
Physical exercise;
Uric acid;
Downs syndrome

Abstract
Background: Downs syndrome (DS) individuals have elevated uric acid (UA) urinary levels.
Objective: To evaluate urinary UA levels variation with physical exercise practice in DS
individuals.
Material and methods: We analysed 29 individuals with DS and 37 individuals without DS
(control group) matched by age and sex. Urinary UA levels were determined by Duncan
method. Creatinine (Cr) was assessed according to the spectrophotometric Jaff method.
Results: We reported that individuals with DS have signicant elevated urinary UA levels
compared to controls (315 123 mmol/mmol vs 245 84 mmol/mmol), and we did not
observe any signicant variation with respect to sex or age. However, up to 20 years a
negative correlation between ratio UA/Cr and age was obtained. This correlation was
positive starting from 20 years. According to our results this correlation is more accentuated in DS individuals. Urinary UA levels decrease 19.0% in DS individuals and 6.4% in
controls when sport is practiced more than occasionally to daily.
Conclusions: Urinary UA is increased in DS individuals. Urinary UA does not vary signicantly according to sex. The daily practice of physical exercise of moderate intensity
reduces the urinary excretion of UA in DS individuals.

a
This work forms part of a project funded by the Fundacin
Inocente, Inocente.
*Correspondence author.
E-mail: acasado@cib.csic.es (A. Casado Moragn).

1138-011X/$ - see front matter 2011 Fundaci Catalana Sndrome de Down. Published by Elsevier Espaa, S.L. All rights reserved.

02_ORIGINAL_ing_1_2013 (3-7).indd 3

11/04/13 13:09

C. Campos Vaquero et al

PALABRAS CLAVE
Ejercicio fsico;
cido rico;
Sndrome de Down

Ejercicio fsico y niveles urinarios de cido rico en sndrome de Down

Resumen
Antecedentes: Los individuos con sndrome de Down (SD) presentan niveles elevados de
cido rico (AU).
Objetivo: Evaluar la variacin producida con la prctica de ejercicio fsico en los niveles
urinarios de AU en individuos con SD.
Material y mtodos: Se ha analizado a 29 individuos con SD de ambos sexos y edades de
4 a 52 aos. Se analizaron 37 individuos sanos, sin trisoma 21 de ambos sexos y edades
de 5-72 aos (controles). Se utiliz el mtodo de Duncan et al para determinar el AU. La
creatinina (Cr) se determin por el mtodo de Jaff, modicado por Varley y Gowenlock.
Resultados: Los valores de AU urinario referenciados a Cr son signicativamente mayores
(p < 0,01) en individuos con SD que en controles (315 123 mmol/mmol frente a 244 83
mmol/mmol), y no varan signicativamente ni con el sexo, ni con la edad. Sin embargo,
tanto en el grupo control, como en el de SD aparece una correlacin negativa entre el
ratio AU/Cr y la edad hasta los 20 aos, que se hace positiva a partir de esta edad. Nuestros resultados muestran una correlacin ms acentuada en personas con SD. El AU disminuye un 19% en SD y un 6,4% en controles cuando el deporte pasa de practicarse ocasionalmente a diariamente.
Conclusiones: El AU urinario est aumentado en individuos con SD. El AU urinario no vara
signicativamente con el sexo. La prctica diaria de ejercicio fsico con intensidad moderada reduce la excrecin urinaria de AU en el SD.

Introduction
In humans, uric acid (UA) is the metabolic end-product of
purines ingested in the diet or produced by the cells by the
action of xanthine oxidase on xanthine and hypoxanthine. It
is mainly excreted in the urine and faeces, and this increases
with a protein rich diet, and after treatment with
corticosteroids and uricosurics. It is found in the blood as
monosodium urate, in much higher concentrations than the
rest of the primates, due to humans lacking the enzyme
urate oxidase. Both the free acid and its urate salts are only
slightly water-soluble and may precipitate and crystallise in
the kidney to form renal calculi. Furthermore, when uric
acid concentrations are high (hyperuricaemia), it can be
deposited in the cartilage tissue, causing a disease known
as gout.
Downs syndrome (DS) is the first clinically defined chromosomal syndrome1, and is caused by the presence of three
copies of chromosome 21 (Lejeune et al., 1959)2. It is one
of the most significant human congenital defects, with an
incidence of 1 in every 700-1000 births3. In 95% of cases it
is due to a primary trisomy of chromosome 21. Between
3-5% may be caused by a translocation of a chromosome 21
to another group D chromosome (13-15), often to 14, or to
another chromosome of group G (21-22)4. Approximately
2-4% of patients with DS have mosaicism, with different
percentages between the normal cell line and the cell line
with trisomy5.
Individuals with DS show a marked hypotonia, with short
stature, overweight, and oblique and palpebral fissures. As
well as the physical and facial characteristics, DS is one of
the main causes of mental retardation and congenital heart
defects, as well as congenital anomalies of the digestive
system, various renal and urological anomalies6-8, changes

02_ORIGINAL_ing_1_2013 (3-7).indd 4

in the immune and endocrine system, a high risk of leukaemia, and the early appearance of Alzheimers disease9.
Urine samples have been used in this study, due the
advantages of obtaining this type of sample, and due to the
lack of these types of studies in DS. Urine samples are often
used for the determination of biochemistry parameters and
biological markers, particularly for compounds with a short
biological life, such as drugs, metals and some currently
used pesticides (Barr et al, 2005)10. Urine has many advantages over other types of specimens, such as blood or cerebrospinal fluid, since it can be obtained non-invasively,
and also provides a sufficiently large volume to be able to
make many determinations. All these advantages make the
urine specimen the ideal choice for population studies.
The objectives of this work were aimed at: analysing the
urine uric acid concentration in individuals with Downs
syndrome, and to determine the influence of diet and performing physical exercise on the urine uric acid levels.

Material and methods

The study was carried out with a group of 29 individuals of
both sexes with DS (13 females and 16 males) and with ages
from 4 to 52 years. They were recruited from day centres,
public schools, state aided special schools, and supervised
ats of the Community of Madrid. Of the 29 individuals with
DS, 26 had complete trisomy, 2 mosaics and 1 translocation.
The study also included a group of 37 healthy individuals of
both sexes and without trisomy 21 (24 females and 13
males), and ages from 5 to 72 years, with the majority
being brothers or sisters of those of the DS group.
The cytogenetic characteristics of the DS series studied
in this work had been previously analysed by peripheral

11/04/13 13:09

Physical exercise and urinary uric acid levels in Downs syndrome

The urine UA levels referenced to Cr were signicantly

higher in individuals with DS than in the control group,
P<.01) (g.1), with means SD of 245 84 mmol/mmol for
the control group and 315 123 mmol/mmol for the DS
group being obtained. In the sample analysed, the UA levels
did not vary signicantly with sex or age. However, there
appeared to be a negative correlation between the UA/Cr
ratio and age up to 20 years both in the controls (r = 0.70;
P<.05), and in DS (r = 0.83; P<.01), which became positive
after this age (g. 2).
The UA did not significantly vary with physical exercise
of moderate intensity, although a decrease of 19.0% was
observed in the DS group, and 6.4% in the control group,
when the performing of exercise was increased from occasionally to daily (fig. 3).
No significant variations were observed in the urinary UA
excretion with diet, although a higher consumption of certain types of food (meat, pulses, nuts and fruit) led to a
slight increase in the UA levels in the urine.

Discussion
The total body UA, as urate, is a balance between production
and elimination. Approximately two-thirds of the urate
produced each day are excreted in the urine, and the other
third is directly eliminated in saliva and intestinal secretions

02_ORIGINAL_ing_1_2013 (3-7).indd 5

400

UA / Cr (mmol/mol)

350
300
250
200
150
100
50
0

Control

DS

Figure 1 Comparison of the uric acid/Creatinine (UA/Cr)

ratio between the group with SD and the control group.
*Indicates signicant differences (p<0.01).

700
UA / Cr (mmol/mol)

Results

450

600
500
400
300
200
100
0

10

20

30

40

50

60

70

80

Age (years)
Control

DS

Figure 2 Changes in the uric acid/Creatinine (UA/Cr) ratio

with age. The graph shows second-order polynomial trend
lines.

UA / Cr (mmol/mol)

blood lymphocyte cultures11, using 3 techniques to examine

the chromosomes in detail: CTG, CBG, and RHG banding.
The proportions found showed a distribution in accordance
with that observed in DS epidemiology studies4, in which
the complete primary trisomy is the most common anomaly, 93.3% in our case.
The analyses were performed on first early morning
urine samples (fasting), in the Department of Cell and
Molecular Medicine of the Spanish National Research Council Biological Research Centre (Departamento de Medicina
Celular y Molecular del Centro de Investigaciones Biolgicas del Consejo Superior de Investigaciones Cientficas
[CSIC]). As well as this urine specimen, a questionnaire was
completed that included sociodemographic data, performing of physical exercise, and dietary habits. The performing
of this study was approved by the CSIC Bioethics Committee. All the participants in the study, or their legal representatives, gave their consent to be included.
The ultraviolet uricase method by Duncan et al12 was
used to determine UA, with slight modifications. The values
obtained were referenced to the creatinine (Cr) determined by the Jaff method13 modified by Varley and
Gowenlock14.
The software SPSS 18.0 was used for the statistical
analysis, with the results expressed as mean standard
deviation (SD). The distribution of the group was determined by means of the Kolmogorov-Smirnov test, showing a
normal distribution for both groups. The Student t test and
the ANOVA test were used for the group comparisons. Significant differences were considered with a P<.05.

500
400
300
200
100
0

Daily

Weekly
Control

Ocasionally
DS

Figure 3 Changes in the uric acid/Creatinine (UA/Cr) ratio

according to the frequency of performing physical exercise.

11/04/13 13:09

6
as a result of bacterial uricolysis15. Elimination is also
affected by diurnal variations: the renal excretion of UA is
reduced and intestinal secretion is increased during sleep16.
Various authors17-20 have observed increased serum levels
of uric acid in DS, which supports the data obtained in this
work on urine specimens, but the origin of this biochemical
anomaly is not completely clear. Coburn et al17, suggested
that the increase in UA levels in blood may be caused by a
decrease in the efficacy in the elimination more than due
to an increase in its synthesis. Nishida et al21 indicated that
glomerular dysfunction may contribute to the hyperuricaemia in DS, although some authors attribute this increase in
UA in DS to changes in glomerular filtration17,18.
The formation of UA may also occur through the xanthine
oxidase system with the subsequent production of a superoxide. Decreases in hypoxanthine and xanthine have been
found in children with DS20, which suggests an increase in
the conversion of hypoxanthine to xanthine, which is then
converted into UA and superoxide.
Puukka et al22 found that the red cell levels of adenosine
deaminase and adenine phosphoryl transferase correlated
with increases in plasma urates in individuals with DS. The
increase in gene dosage of double-stranded RNA-specific
adenosine deaminase (coded in chromosome 21) can cause
an increase in the activity of the enzyme, and could contribute to the increase in UA in DS.
Individuals with DS show a significant increase in mitochondrial DNA mutations and a reduction in the gene
expression of adenosine triphosphatase, an enzyme responsible for the biosynthesis of adenosine triphosphate23. The
decrease in adenosine triphosphate leads to the accumulation of the adenosine deaminase that is deaminated by
adenosine monophosphate deaminase into inosine
monophosphate, and then converted by inosine 5-monphosphate into inosine, which can enter into the blood and
produce hypoxanthine. Xanthine oxidase converts hypoxanthine into xanthine, with the subsequent formation of even
more superoxide. The intracellular hypoxanthine formed
from inosine can also enter the blood and be converted by
xanthine oxidase to UA, with the formation of superoxide.
This mechanism could partly explain the increase in UA
levels.
The fact that a negative correlation was found in this
study between the UA/Cr ratio and age up to 20 years,
which became positive after this age could be attributed
to, the relatively higher weight of the internal organs, an
increase in the DNA/protein ratio, and the accelerated
growth of the organs during childhood, facts that were
already shown by Stapleton et al24. The lower musculature
in the younger group with DS could explain these results. As
regards gender, our results agree with these obtained by
Mrcia E. Garcez et al25, who also did not find differences
in the serum uric acid levels between males and females
with DS.
The decrease in urine UA levels obtained in this study, as
regards performing physical exercise, has also been
observed in samples of muscle and blood26, as well as in
saliva samples27. Slater et al28, in a study conducted in Jerusalem, observed that, in active males who performed
physical exercise, the serum uric acid concentration was
significantly lower than in inactive males. They also

02_ORIGINAL_ing_1_2013 (3-7).indd 6

C. Campos Vaquero et al
obtained an inverse correlation between the serum uric
acid concentration and physical activity. Although human
cells lack the enzyme uricase that converts UA into allantoin, if the UA is subjected to systems that produce free
radicals and reactive oxygen species (ROS), they could
produce, by means of non-enzymatic oxidation reactions,
several oxidation products such as, allantoin, glyoxylic
acid, urea, oxalate, etc.29. It has also been observed that
UA can be oxidated by other agents such as chromosome
C30. All these could partly explain the decrease in UA with
the performing of physical exercise by the increase in the
generation of free radicals and the ROS that it entails.
The most important point of this work has been the
confirmation that physical exercise performed daily
decreases urine UA levels in DS. Thus, the regular practising of sport could help to improve the quality of life of
people with DS.

Conclusions
Urine UA is increased in people with DS.
Urine UA does vary significantly between males and
females.
Up to 20 years of age the UA/Cr ratio decreases, but
later it gradually increases.
The regular performing of physical exercise reduces urinary UA excretion, but not significantly in the population
studied.
Diet did not significantly influence the urine UA levels in
the DS group or in the control group.
The limitations of the study are that individuals with
Downs syndrome generally tend to be sedentary, and it is
difficult to find individuals who perform exercise regularly.
Thus the strength of publishing works like ours, that show
the advantages that performing physical exercise may
bring, should help raise awareness that it is a tool that
could improve their quality of life

   
Authors declare not to have any conict of interests.

Acknowledgements
Our thanks to all those with Downs syndrome, their
families, and all the volunteers, whose unselsh
participation has made this work possible. We would also
like to thank the centre collaborators and the Fundacin
Inocente, Inocente, which without its help this work could
not have been done.

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3:229-33.
19. Nagyov A, Sustrov M, Raslov K. Serum lipid resistance to
oxidation and uric acid levels in subjects with Downs syndrome.
Physiol Res. 2000;49:227-31.
20. Zitnanov I, Korytr P, Aruoma OI, Sustrov M, Garaiov I,
Muchov J, et al. Uric acid and allantoin levels in Downs
syndrome: antioxidant and oxidative stress mechanisms? Clin
Chem Acta. 2004;341:139-46.
21. Nishida YIA, Kobayashi M, Maruki K, Oshima Y. Renal impairment
in urate excretion in patients with Downs syndrome. J
Rheumatol. 1979;6:103-7.
22. Puukka R, Puukka M, Leppilampi M, Linna SL, Kouvalainen K.
Erythrocyte adenosine deaminase, purine nucleoside
phosphorylase and phosphoribosyltransferase activity in patients
with Downs syndrome. Clin Chim Acta. 1982;126:275-81.
23. De Haan JB, Wolvetang EJ, Cristiano F, Iannello R, Bladier C,
Kelner MJ, et al. Reactive oxygen species and their contribution to
pathology in Down syndrome. Adv Pharmacol. 1997;38:379-402.
24. Stapleton FB, Linshaw MA, Hassanein K, Gruskin AB. Uric acid
excretion in normal children. J Pediatr. 1978;92:911-4.
25. Garcez ME, Peres W, Salvador M. Oxidative stress and
hematologic and biochemical parameters in individuals with
Downs syndrome. Mayo Clin Proc. 2005;80:1607-11.
26. Hellsten Y, Tullson PC, Richter EA, Bangsbo J. Oxidation in
human skeletal muscle during exercise. Free Radic Biol Med.
1997;22:169-74.
27. Owen-Smith B, Quiney J, Read J. Salivary urate in gout,
exercise, and diurnal variation. The Lancet. 1998;351:1932.
28. Slater PE, Kaufmann NA, Friedlander Y, Stein Y. Effects of
smoking and physical activity on serum uric acid in a Jerusalem
population sample. Ann Hum Biol. 1985;12:179-84.
29. Grootvel M, Halliwell B. Measurement of allantoin and uric acid
in human body uids. A potential index of free-radical reactions
in vivo? Biochem J. 1987;243:803-8.
30. Martens ME, Storey BT, Lee CP. Generation of allantoin from
the oxidation of urate by cytochrome c and its possible role in
Reyes syndrome. Arch Biochem Biophys. 1987;253:91-6.

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Rev Med Int Sindr Down. 2013;17(1):8-12

INTERNATIONAL
MEDICAL REVIEW
ON DOWNS SYNDROME

www.fcsd.org

www.elsevier.es/sd

ORIGINAL ARTICLE

Maternal age: a controversial factor in trisomy 21

M. Vashist and Neelkamal*
Department of Genetics, Maharshi Dayanand University, Haryana, India
Received on March 1, 2012; accepted on December 21, 2012

KEYWORDS
Trisomy 21;
Aneoploidy;
Nondisjunction;
Maternal age;
Down syndrome

Abstract
Background: Downs syndrome (DS) is the most common autosomal aneuploidy in human
beings and is characterized by a complex phenotype including characteristic facial
features, skeletal appearance and it is most commonly diagnosed congenital malformation/
mental retardation syndrome. Although advanced maternal age is a well established risk
factor for the etiology of DS, controversy over it still continues.
Objective: The study was carried out to nd the effect of maternal age in the etiology of
trisomy-21.
Material and methods: Present study has been conducted on DS cases from various
districts of Haryana State. DS cases were subjected to detailed morphological and
cytogenetic analysis.
Results: In the present study more than eighty percent of DS children were born to young
mothers of <35 years and less than twenty percent to mothers age >35 years. DS cases
born to mothers of age less than 30 years were 69.5%. Mean age of mother was 29.5
years. Partial correlation coefcient between mothers age and number of DS cases
(keeping father age constant) was calculated as r = 0.315.
Conclusion: Present study is not in favour of the effect of advanced maternal age on the
occurrence of DS child. It can be concluded that risk of DS cases is not only due to the
advanced maternal age and some others factors (genetic and environmental) may be
involved in the formation of a trisomic zygote. Future studies are required to investigate
the various factors that regulate the segregation & recombination in humans.

* Correspondence author.
E-mail: neelgenetics@yahoomail.com (Neelkamal).
1138-011X/$ - see front matter 2011 Fundaci Catalana Sndrome de Down. Published by Elsevier Espaa, S.L. All rights reserved.

03_ORIGINAL_ingl_1_2013 (8-12).indd 8

11/04/13 13:09

Maternal age: a controversial factor in trisomy 21

PALABRAS CLAVE
Trisoma 21;
Aneuploida;
No disyuncin;
Edad materna;
Sndrome de Down

Edad materna: un factor de controversia en la trisoma 21

Resumen
Antecedentes: El sndrome de Down (SD) es la aneuploida autosmica ms frecuente en
humanos. Se caracteriza por un fenotipo complejo que incluye rasgos faciales caractersticos y una apariencia esqueltica; constituye la malformacin congnita/sndrome de
retraso mental ms diagnosticado. Aunque la edad avanzada de la madre es un factor de
riesgo bien establecido para la etiologa del SD, sigue habiendo opiniones contrapuestas
al respecto.
Objetivo: El estudio se llev a cabo para descubrir el efecto de la edad materna en la
etiologa de la trisoma 21.
Material y mtodos: Este estudio se realiz contemplando casos de SD de diferentes barrios del estado de Haryana (India). Los casos de SD estaban sujetos a un anlisis morfolgico y citogentico detallado.
Resultados: En este estudio, ms del 80% de los nios con SD haban nacido de madres
jvenes, de < 35 aos, y menos del 20%, de madres de > 35 aos. Los casos de SD nacidos
de madres con edades inferiores a 30 aos supusieron el 69,5%. La media de edad de la
madre eran 29,5 aos. El coeciente de correlacin parcial entre la edad de la madre y
el nmero de casos de SD (manteniendo constante la edad del padre) se calcul como
r = 0,315.
Conclusin: El resultado de este estudio no es favorable al efecto de la edad materna
avanzada en la incidencia de nios con SD. Podemos concluir que el riesgo de casos de SD
no solamente se debe a la edad avanzada de la madre y que puede haber otros factores
(genticos y ambientales) que afecten la formacin de un cigoto trismico. Es necesario
realizar ms estudios para investigar los diferentes factores que regulan la segregacin y
la recombinacin en humanos.

Introduction
Downs syndrome is the most common autosomal aneuploidy
in human beings, caused by a gene dosage-imbalance
resulting from human chromosome-21 trisomy and it is
characterized by a complex phenotype including
characteristic facial features, skeletal appearance, low
mental level, hearing loss and developmental delay1. It is a
cosmopolitan disease, having been reported in nearly all
countries and ethnic groups. Although advanced maternal
age is a well established risk factor for trisomy 21 Downs
syndrome, much remains to be learnt about the basis of the
maternal age effect. For example, It is still uncertain
whether the chronological age of mother or the physiological
age of the ovary has any biological and clinical relevance. If
oocyte reduction with advancing age is the basis of the
maternal age effect, as suggested by Warburton2, then
women, who have a reduced number of oocytes for other
reasons might have an increased risk for a conception with
trisomy. Frequency of nondisjunction increases with the
maternal age. This increased risk is due to factor that
adversely affects meiotic chromosome behavior as a woman
ages.
According to well documented studies it was found
that excluding the eventual effects of viral disease,
x-rays and others risk exposures, free trisomy 21 very
often arises as second meiotic error and its frequency
increases with ageing of mother i.e. 35 years and over3.
It has recently been shown that 95% of cases of trisomy
21 appear to result from nondisjunction occurring in the

03_ORIGINAL_ingl_1_2013 (8-12).indd 9

first meiotic division in the ovum4. Several theories have

been proposed to explain the increased incidences of
Downs syndrome with advanced maternal age. Another
hypothesis proposes that structural, hormonal and immunologic changes that occur in the uterus with advanced
age produce an environment which is less able to reject
a developmentally abnormal embryo5. Although the
underlying cause of an extra copy of chromosome 21 has
been known for a long time, the phenotype to genotype
relationship is just beginning to be understood and many
questions about the molecular pathophysiology of the
condition have not yet been answered. These and other
hypothesis are not mutually exclusive and it is possible
that a combination of factors is responsible for the relationship between the incidence of trisomy 21 and
advanced maternal age6. Still majority of relations of
maternal age to nondisjunction has been described as
one of the most important problem to be solved in
Downs syndrome and in human cytogenetics.

Material and methods

Present study has been conducted on 200 cases of Downs
syndrome from 30 centers of 12 districts of Haryana.
Detailed history with complete data on course of pregnancy,
age of the parents at the birth of the child and neonatal
period of Downs syndrome patients were taken. Downs
syndrome cases were subjected to detailed morphological
and cytogenetic analysis.

11/04/13 13:09

10

M. Vashist and Neelkamal

25

Frequency (%)

20
< 30
> 30

15
10
5

Figure 2 Percentage frequency of Downs syndrome cases

having mothers age <30 and >30.
40
>

-4
0

-3
7

38

-3
4

35

32

-3
1
29

-2
8

-2
5

26

-2
2

23

20

<

20

0
Age (years)

Figure 1 Percentage frequency of maternal age in Downs

syndrome patients.

mosaicism the mothers were of between 28-34 years (table

2). In free trisomy 21 cases maternal age at pregnancy was
below 30 in 67.3% cases and above 30 in 27.2% cases (table
3). In maximum cases of free trisomy 21 (50.2%) mothers
age was between 26-30 years (table 4). Present study sup-

Results
Marked variation was noticed amongst the age of the
mother of a Downs syndrome child. It varied from 17 years
to 46 years. Maximum (23.5%) Downs syndrome children
were born to the mothers of age 26-28 year (g. 1). To
know the role of maternal age in Downs syndrome six
different age groups were made. Mean age of mother was
29.5 years in the Downs syndrome cases. Downs syndrome
cases born to mothers of age less than 30 years were 69.5%
and to mothers aged more than 30 years were 30.5% (table
1 and gure 2). Age and sexwise analysis of Downs syndrome
cases in different age group of parents showed that more
number of male Downs syndrome children were born to
parents of 25 to 30 years of age. Partial Correlation
coefcient between mothers age and number of Downs
syndrome cases (keeping father age constant) was
calculated as r = 0.315, which showed that increase risk of
Downs syndrome was not due to exclusively mothers age
factor.
In case of free trisomy, mothers age at pregnancy was
between 20-40 years. In the case of translocation and

Table 2 Maternal age in cytogenetically analysed

cases
N.

Cytogenetics of Downs N. of
syndrome cases
cases (%)

Age of mother
(years)

Free trisomy 21

94.5

20-40

Translocation 14; 21

1.1

28

Mosaic for
translocation 21; 21

1.1

32

Mosaic for free trisomy 1.1

21

34

Normal cytogenetics
2.2
with Downs syndrome
phenotype

25-28

Table 3 Cytogenetics of Downs syndrome cases and

maternal age (<30 years and >30 years)
Table 1 Distribution of maternal age in Downs syndrome
(D.S.) & Control cases (n=200)
N. of mothers
Age range
(years)
SD
Control

Percentage
SD

Control

< 20

15

4.5

7.5

21-25

60

71

30.0 69.5

35.5 86.0

26-30

70

86

35.0

43.0

31-35

27

16

13.5

8.0
30.5

> 35

34

12

Total

200

200

03_ORIGINAL_ingl_1_2013 (8-12).indd 10

17.0

14.0
6.0

Cytogenetics

< 30 years

> 30 years

Free trisomy 21

(67.3%)

(27.2%)

Translocation 14; 21

1.1%

Mosaic for
translocation 21; 21

1.1%

Mosaic for free

trisomy 21

1.1%

Normal cytogenetics with

Downs syndrome
phenotype

1.1

1.1

Total

(69.5%)

(30.5%)

11/04/13 13:09

Maternal age: a controversial factor in trisomy 21

Table 4

Maternal age in free trisomy 21 cases

Mothers age (years)

Downs syndrome
cases (%)

< 20

(4.9)

21-25

(12.2)

26-30

(50.2)

31-35

(20.1)

36-40

(7.1)

> 40

(67.3)*
(27.2)**

*Age below 30.

**Age above 30.

ports the compromised microcirculation hypothesis, which

suggests that greater risk factor for non disjunction among
younger women is the presence of a susceptible exchange
pattern7.

Discussion
Though maternal age was dismissed by the Penrose8 as
insignicant in the etiology of Downs syndrome, controversy
over maternal age continues, mainly because an equivocal
data could not be obtained either supporting or rejecting
it9,10. Important factors in the conception of trisomies are
delayed fertilization, advanced maternal age and increased
satellite association11. Other factors such as physical,
biological and chemical mutagens, have also been found to
cause non disjunction6. The most accepted statement is
that the risk of the disease increases exponentially with the
ageing of the mother, as 1st recognized by Shuttleworth
(1909). The analysis of Downs syndrome patients in the
present study depicted that mean maternal age was 29.5
years for Downs syndrome cases. In the western studies the
mean maternal age at the conception of Downs syndrome
children was found to be 34.4 years12. There must be other
factors playing role in birth of Downs syndrome child. In
another study, the percentage of trisomies among all
clinically recognized pregnancies climbed from 2% for
women <25 years of age to 35% for women >40 years of
age7. On contrary, reports from Sweden revealed that
despite the rising maternal age, there was no increase in
the number of births of children with Downs syndrome13.
Present study reveals that more than 80% of Downs syndrome children were born to young mothers of <35 years
and less than 20% born to mothers age >35 years (table
5)14,15. The result of present study is not in favour of the
effect of age of mother on the occurrence of Downs syndrome child. Therefore Shuttleworth explanation does not
provide answer to the cases where Downs syndrome child
is born to a young mother. It has recently been shown that
95% of cases of trisomy 21 appear to result from nondisjunction occurring in the 1st meiotic division on the ovum16.
Along with the advanced maternal age, altered recombina-

03_ORIGINAL_ingl_1_2013 (8-12).indd 11

11
tion pattern is the only other factor that is consistent with
maternal meiotic nondisjunction17.
The explanation for increased risk of nondisjunction to
maternal age is suggested by hyposthesis that the very long
prophase of meiosis, in the state of suspended animation of
the ovum before the 1st meiotic division at ovulation, alter
the segregation of the chromosome resulting in nondisjunction18. The compromised microcirculation hypothesis
explains the occurrence of aneuploidy in primary and secondary oocytes, sperm precursor cells, tumor and embryonic cells. It also explains why women of all reproductive
ages may have a Downs syndrome child19. It was also suggested that the greatest risk factor for nondisjunction
among younger women is the presence of a susceptible
exchange pattern. It was hypothesized that environmental
and age related insults accumulate in the ovary as a woman
ages, leading to malsegregation of oocytes with stable
exchange patterns. It is the risk, due to recombination
independent factors, that would be most influenced by
increasing age, leading to the observed maternal age
effect7.
One reason for urgency in gaining an understanding of
the causes of nondisjunction and the maternal age effect is
that many professional women are effectively delaying
child bearing until their mid-thirties or later, when their
risk of having a trisomic child increases significantly. In
some populations there are already indications that this
delay of pregnancy is beginning to produce detectable
increase in the incidence of Downs syndrome20. Much more
data are needed on trisomic incidence in offsprings of very
young mothers. This would help to determine whether the
maternal age effect is indeed restricted to women of older
reproductive ages, as is now widely believed. Such data
would also be helpful in better assessment of the hypothesis involving hormonal imbalance. A multidisciplinary
approach to know the trisomy induction and influence of
maternal age is required. Molecular approaches to the classical ones of biochemistry, cell biology, cytogenetics, epidemiology, genetics and physiology may be considered. We
hope that eventually knowledge of what is responsible for
natural aneuploidy may be identified and further damage
to the oocyte could be prevented.

Table 5 Maternal age and the percentage of Downs

syndrome (DS) cases in India
Age range
(years)

DS in other
parts of
India (%)

DS in present Controls
study (%)
(normal) (%)

< 20

6-8

4.5

7.5

21-25

38-43

30.0

35.5

26-30

21-30

35.0

43.0

31-35

12-18

13.5

8.0

36-40

4-8

15.0

4.0

> 40

0-3

2.0

2.0

11/04/13 13:09

12

Funding
Funded by UGC.

   
Authors declare not to have any conict of interests.

Acknowlegment
The authors are thankful to Arpan & other Institutes of
mentally retarded children in Haryana, parents and
guardians for providing kind co-operation and information.
The work supported in parts by UGC (University Grants
commission major research project grant) & ICMR (Indian
council of medical research project grant vide
5/4-4/13/M/2006-NCD -1).

References
1. Girirajan S. Parental-age effects in Down syndrome. J Genetics.
2009;88:1-7.
2. Warburton D. The effect of maternal age on the frequency of
trisomy: change in meiosis or in utero selection. Prog. Clinical
Biological Res. 1989;311:165-81.
3. Lejeune J. Chromosome in trisomy 21. Ann NY Acad Sci. 1970;
171:381.
4. Pangalos C, Avramopoulos D, Blouin JL, Raoul O, De Blois MC,
Marguerite P. Understanding the mechanism(s) of mosaic
trisomy 21 by using DNA polymorphism analysis. Am J Hum
Gene. 1994;54:473-81.
5. Epstein CJ. Down syndrome (trisomy 21). En: Scriver CR,
Beaudet ALSly, WS Valle D (eds). The metabolic and molecular
basis of inherited disease. New York: Mcgraw-Hill; 2001. p.
1223-56.

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6. Ghalib MA, Isaac GS. Paternal consanguinity in Down syndrome.
Ann Natl Acad Med Sci (India). 1991;27:43-6.
7. Lamb NE, Shaffer KJ, Feingold E, Sherman S L. Association
between maternal age and meiotic recombination for trisomy
21. Am J Hum Genet. 2005;6:91-9.
8. Penrose LS. The relative effects of paternal and maternal age
in mongolism. J Genet. 1933;27:219-4.
9. Carothers AD. Controversy concerning paternal age effect in
47, + 21 Down syndrome. Hum Genet. 1988;78:384-5.
10. Hook EB, Cross PK. Factual statistical and logical issues in the
search for paternal age effect for Down syndrome. Hum Genet.
1990;85:387-8.
11. Fox D, Sindwani V. Satellite association. Karyogram. 1985;11:3.
12. De Grouchy J, Turleau C. Clinical atlas of human chromosomes.
New York: John Wiley and Sons; 1983. p. 319.
13. Frid C, Drott P, Otterblad Olausson P, Sundelin C, Anneren G.
Maternal and neonatal factors and mortality in children with
Down syndrome born in 1973-1980 and 1995-1998. Acta
Paediatr. 2004;93:106-12.
14. Suttur SM, Nallur BR. Inuence of advanced age of maternal
grandmothers on Down syndrome. BMC Med Genet. 2006;7:4.
15. Jyothy A, Kumar KS, Mallikarjuna GN, Babu Rao V, Uma Devi B,
Sujatha M, et al. Parental age and the origin of extra
chromosome 21 in Down syndrome. J Hum Genet. 2001;46:
347-50.
16. Kotzot D, Schinzel AA. Paternal meiotic origin of der (21;21)
(q10;q10); mosaicism [46,xx/46,xx, der (21;21) (q10;q10);
+21] in a girl with mild Down syndrome. European J Hum
Genet. 2000;8:709-12.
17. Sherman SL, Allen EG, Bean LH, Freeman SB. Epidemiology of
Down syndrome. Ment Retard Dev Disabil Res Rev. 2007;13:221-7.
18. Snusted DP, Simmons MJ. Variation in chromosome number and
structure. In: Principle of genetics. 2nd ed. John Wiley and
sons, Inc.; 2000. p. 150-1.
19. Gualden ME. Maternal age effect: the enigma of Down
syndrome and other trisomic conditions. Mut Res. 1992;296:
69-88.
20. Staples AJ, Sutherland GR, Haan EA, Clisby S. Epidemiology of
Down syndrome in South Australia. Am J Med Genet. 1991;49:
1014-24.

11/04/13 13:09

Rev Med Int Sindr Down. 2013;17(1):13-15

INTERNATIONAL
MEDICAL REVIEW
ON DOWNS SYNDROME

www.fcsd.org

www.elsevier.es/sd

CASE REPORT

Unusual cause of respiratory distress: Morgagni hernia associated

to Downs syndrome
S. Degerli*, N. Dereli, S. Sahin and E. Ozayar
Anesthesiology-Reanimation Department, Kecioren Research and Training Hospital, Ankara, Turkey
Received on September 14, 2012; accepted on December 21, 2012

KEYWORDS
Morgagni hernia;
Downs syndrome;
Respiratory distress

PALABRAS CLAVE
Hernia de Morgagni;
Sndrome de Down;
Dicultad respiratoria

Abstract
Morgagni hernia (MH) is a rare diaphragmatic hernia with 2% rate of congenital
diaphragmatic hernias. Is reported Downs syndrome (DS) the most common chromosomal
anomaly. There is a wide range variation among individuals clinically by its characteristic
features and associated systemic malformations. The coexistence of Morgagni hernia and
DS is reported approximately 20%.
A female patient with DS was admitted to emergency department for evaluation of
recurrent pneumonia accompanied by persistent dry cough and fever. In the case the
radiographic abnormality was actually found to be MH with intestinal loops in the right
thorax. We report this case to notify an asymptomatic association between DS and MH.

          

de Down
Resumen
La hernia de Morgagni (HM) es una hernia diafragmtica poco frecuente, con un ndice de
hernias diafragmticas congnitas del 2%. El sndrome de Down (SD) es la anomala cromosmica ms frecuente noticada. Desde el punto de vista clnico, hay una variacin
muy amplia entre individuos por sus rasgos caractersticos y las malformaciones sistmicas asociadas. La coexistencia de hernia de Morgagni y sndrome de Down se ha noticado en aproximadamente un 20%.
En el servicio de urgencias se ingres a una mujer con SD para evaluar una neumona
recurrente acompaada de ebre y tos seca persistente. En este caso, se observ que la
anomala radiogrca era en realidad HM, con asas intestinales en el lado derecho del
trax. Presentamos este caso para dejar constancia de una asociacin asintomtica entre
el SD y la HM.

* Correspondence author.
E-mail: drsemih@gmail.com (S. Degerli).
1138-011X/$ - see front matter 2011 Fundaci Catalana Sndrome de Down. Published by Elsevier Espaa, S.L. All rights reserved.

04_CASO_ingl_1_2013 (13-15).indd 13

11/04/13 13:09

14

S. Dergerli et al

Introduction
Morgagni hernia (MH) is a congenital diaphragmatic
herniation due to an anteriorly located diaphragmatic
defect. Its rare, with an incidence of 1 in 2200 births and
accounts for the 3-5% of all diaphragmatic hernias1. Patients
usually has a respiratory distress within a few days after
birth. Diagnosis of MH in adults is incidental, as it is usually
asymptomatic, but sometimes it may be challenging. 50% of
MH are associated with congenital anomalies, congenital
heart disease, neural tube defects and chromosomal
abnormalities2. Association with Downs syndrome (DS) is
rarely reported in literature3-6. Here we report a MH
associated to DS in an adult patient presenting to our clinic
with respiratory distress.

Case Report
A 22-year old female patient, with a diagnosis of DS, was
admitted to emergency department with fever and dyspnea.
The patient had been regularly followed and she had no
comorbidity except DS. She had a 1 week history of
persistent dry cough. Initial physical examination revealed
39.2 C fever, cyanosis and diminished breath sound in the
right lower lung. Leukocytosis and severe respiratory
acidosis were noted in laboratory evaluation. Biochemical
parameters were normal. Hemodynamically stable patient
was treated with nasal oxygen and closely monitored.
Further evaluation with chest x-ray showed intestinal loops
in the right thorax with inltrative radio opacity consistent
with pneumonia (g. 1). The left lung was out of pathology.
Thorax computerized tomography confirmed the diagnoses of intestinal herniation through diaphragm and infiltration. The localization and morphology of the hernia was
consistent with MH (fig. 2). The patient was transferred to
intensive care unit (ICU) for further diagnostic work up.
During ICU follow up, respiratory distress and Glasgow
coma score of the patient progressively deteriorated and
the patient was intubated. Under mechanical ventilation
respiratory distress and acidosis progressively improved.

Figure 1
x-ray.

Intestinal loops are seen in the right thorax on chest

04_CASO_ingl_1_2013 (13-15).indd 14

Patient was treated with Levofloxacin with the diagnosis of

community acquired pneumonia. A rapid antibiotic response
was observed and leukocytosis and fever regressed. On the
2nd day chest x-ray, intestinal loops in the thoracic cavity
disappeared leaving an infiltration behind. Patient was followed for eight days and extubated. After twelve days of
follow up, patient was transferred to ward.
At the ward, patient was treated with nasal oxygen.
Levofloxacin was stopped on the 14th day of therapy. On the
2nd day of ward follow up, progressive dyspnea and cyanosis
developed. Patient was again transferred quickly to ICU
with the thought of a recurrence of the diaphragmatic hernia (DH) and possibility of rapid clinical deterioration.
Patient was started on oxygen therapy and closely monitored. Again chest x-ray showed intestinal segments on the
right thoracic cavity. During follow up no further invasive
oxygen replacement was needed and respiratory acidosis
regressed with oxygen facial mask. On the same day of
admission the intestinal loops disappeared on the chest
x-ray. After patient clinically improved she was transferred
to department of surgery for further surgical intervention
for her life threatening recurrent hernia.

Discussion
MH is a rare diaphragmatic defect. The actual pathogenesis
is not clear but hypothesized that its a result of failure of
normal closure of the pleuroperitoneal folds7. DH have been
associated with chromosomal abnormalities, especially
trisomies 18, 13 and 21. Association with Trisomy 21 is rare.
Studies suggest an increased incidence of both MH and DS in
Saudi Arabia and this reects the importance of genetics as
an etiologic factor. DHs are usually left sided and right
sided cases compromise 11%, bilateral herniation only 2% of
all DH. Bilateral herniations are usually associated with
other congenital anomalies8.
In neonatal period DH presents with respiratory distress
whereas adult patients mostly present with nonspecific
gastrointestinal symptoms, recurrent lower respiratory
tract infections and usually with an insidious onset. Pre-

Figure 2

The diagnosis is conrmed with CT.

11/04/13 13:09

Unusual cause of respiratory distress: Morgagni hernia associated to Downs syndrome

senting with recurrent pneumonia in DS causing a diagnosis
of MH have been reported in 2 cases and successfully
treated after surgery5. Our patient also presented with
pneumonia accompanying MH. However after resolution of
pneumonia, recurrence of herniation decompensated
patient and respiratory support was needed. MH - DS association presenting with respiratory distress have been
reported but different from other cases, our patient needed further ICU follow up and invasive respiratory support9,10.
Hernia diagnosis is made with chest x-ray and visualization of herniated abdominal content into thoracic cavity.
Surgery is the definitive treatment modality. In our case,
herniated bowel segments were visualized at the initial
chest x-ray. Further radiological evaluation was needed due
to progressive clinical deterioration. But no other viscera
were noted in thoracic cavity.

Conclusion
MH - DS association is rare entity but it may be a diagnostic
challenge of patient presenting with respiratory failure.
Clinicians should keep in mind that patients with Downs
syndrome can have different anomalies and recurrent
pneumonia, dyspeptic complaints and especially life
threatening respiratory distress may be the only symptoms
of MH.

04_CASO_ingl_1_2013 (13-15).indd 15

15

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