ISSN: 1138-011X Scopus, EMBASE/Excerpta Medica, … · M. Cruz Hernández J. Moreno Hernando S. M. Pueschel ... dela, Research Director of ... (315 ± 123 mmol/mmol vs 245 ± 84 mmol/mmol),

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DSINTERNATIONAL MEDICAL REVIEW

ON DOWN’S SYNDROME

Volume 17•Number 1

January-April

2013Contents Editorial1 25th Anniversary of the Centre Mèdic Down Josep M. Corretger Rauet

Original articles3 Physical exercise and urinary uric acid levels in Down’s

syndrome C. Campos Vaquero, R. Guzmán Martínez, E. López-Fernández

and A. Casado Moragón

8 Maternal age: a controversial factor in trisomy 21 M. Vashist and Neelkamal

Case report13 Unusual cause of respiratory distress: Morgagni hernia

associated to Down’s syndrome S. Degerli, N. Dereli, S. Sahin and E. Ozayar

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Editorial CommitteeEditor: Josep M. CorretgerEditor-in-Chief: Agustí SerésEditorial and Coordination: Katy Trias Trueta

Medical AdvisersF. Ballesta MartínezM. Cruz HernándezJ. Moreno HernandoS. M. Pueschel (USA)

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The aim of SD REVISTA MÉDICA INTERNACIONAL SOBRE EL SÍNDROME DE DOWN (INTERNATIONAL MEDICAL JOURNAL ON DOWN’S SYNDROME) is, on the one hand, to gather cur-rent knowledge on the medical aspects of Down’s Syndrome, and to continuously review and update this, from the most promising advances in basic sciences, such as molecular biology and genetics, to daily clinical practice; and on the other hand, to look at those psychopedagogical �� with Down’s Syndrome. SD will consider publishing clinical or research articles associated with all branches of Down’s Syndrome.

��Cardiology: J. CasaldàligaDermatology: J. FerrandoDietetics-nutrition: N. EgeaEndocrinology: A. GodayMaxillofacial Surgery: A. MonnerGenetics: A. SerésGeriatrics: C. FarriolsGynaecology: J. CararachGeneral Medicine: A. GarnachoChild Neurology: A. NascimentoAdult Neurology: S. FernándezDentistry and Orthodontics: M. A. MayoralChild Ophthalmology: A. GalánAdult Ophthalmology: J. Puig, S. SimónEar, Nose and Throat: J. DomènechPaediatrics: J. M. Corretger, M. HernándezPsychology: B. GarvíaPsychiatry: J. BarbaTraumatology and Orthopaedics: F. Torner

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

EDITORIAL

25th Anniversary of the Centre Mèdic Down

Josep M. Corretger Rauet

Paediatrician, Medical Director of Centre Mèdic Down, Barcelona, Spain

It is 25 years since the Centre Mèdic Down (CMD) opened its doors under the auspices of the Fundació Catalana Sín-drome 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 peo-ple with Down’s syndrome (DS), complementary to the neu-romotor 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 De-cember with a distinguished academic event in the Official Medical College of Barcelona (COMB). The event consisted of the wholehearted support of the Catalonian Health Au-thorities 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 Down’s Syn-drome and Alzheimer Centre, was presented. Drs. Jordi Camí, Director of the Pasqual Maragall Alzheimer Founda-tion, Juan Fortea, Neurology Specialist of the Memory Unit of the Hospital de Sant Pau of Barcelona, and Sebastià Vi-dela, 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 unthink-able 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 Down’s Syndrome and Alzheimer Unit.

01 EDITORIAL ingl (1-2).indd 1 11/04/13 13:08

2 Josep M. Corretger Rauet

by the rest of the staff of the Centre, particularly the Inter-nal 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 Down’s syndrome. From A to Z, published by the FCSD itself in Barcelona in 2008. Paediatricians from Catalonia and Ecuador, including Dr. Ernesto Quiñonez (who hosted the meeting), have collaborated in its publication since its first 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 neu-rodevelopment and sleep in children with DS, and were given by this author and Dr. María Dolores de la Calzada, Consultant Neurophysiologist of the FCSD. The lectures took place in the Quito Hospital Metropolitano and in the El Triángulo 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 fami-lies and the professionals of the Centre is exemplary, thus helping to achieve the proposed aims of improving the de-velopment 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 síndrome de Down. De la A a la Z.

01 EDITORIAL ingl (1-2).indd 2 11/04/13 13:08


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ORIGINAL ARTICLE

Physical exercise and urinary uric acid levels in Down’s syndromea

C. Campos Vaquero, R. Guzmán Martínez, E. López-Fernández and A. Casado Moragón*

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

KEYWORDSPhysical exercise;Uric acid;Down’s syndrome

AbstractBackground: Down’s syndrome (DS) individuals have elevated uric acid (UA) urinary le-vels.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 Jaffé method. Results: We reported that individuals with DS have significant elevated urinary UA levels compared to controls (315 ± 123 mmol/mmol vs 245 ± 84 mmol/mmol), and we did not observe any significant 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 accen-tuated 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 signifi-cantly according to sex. The daily practice of physical exercise of moderate intensity reduces the urinary excretion of UA in DS individuals.

aThis work forms part of a project funded by the Fundación Inocente, Inocente.

*Correspondence author.E-mail: [email protected] (A. Casado Moragón).

02_ORIGINAL_ing_1_2013 (3-7).indd 3 11/04/13 13:09

4 C. Campos Vaquero et al

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.

Down’s syndrome (DS) is the first clinically defined chro-mosomal 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

in the immune and endocrine system, a high risk of leukae-mia, and the early appearance of Alzheimer’s 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 advan-tages over other types of specimens, such as blood or cer-ebrospinal 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 Down’s syndrome, and to determine the influence of diet and per-forming 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 flats 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

PALABRAS CLAVEEjercicio físico;Ácido úrico;Síndrome de Down

Ejercicio físico y niveles urinarios de ácido úrico en síndrome de Down

Resumen Antecedentes: Los individuos con síndrome de Down (SD) presentan niveles elevados de ácido úrico (AU).Objetivo: Evaluar la variación producida con la práctica de ejercicio físico en los niveles urinarios de AU en individuos con SD. Material y métodos: Se ha analizado a 29 individuos con SD de ambos sexos y edades de 4 a 52 años. Se analizaron 37 individuos sanos, sin trisomía 21 de ambos sexos y edades de 5-72 años (controles). Se utilizó el método de Duncan et al para determinar el AU. La creatinina (Cr) se determinó por el método de Jaffé, modificado por Varley y Gowenlock. Resultados: Los valores de AU urinario referenciados a Cr son significativamente mayores (p < 0,01) en individuos con SD que en controles (315 ± 123 mmol/mmol frente a 244 ± 83 mmol/mmol), y no varían significativamente ni con el sexo, ni con la edad. Sin embargo, tanto en el grupo control, como en el de SD aparece una correlación negativa entre el ratio AU/Cr y la edad hasta los 20 años, que se hace positiva a partir de esta edad. Nues-tros resultados muestran una correlación más acentuada en personas con SD. El AU dis-minuye un 19% en SD y un 6,4% en controles cuando el deporte pasa de practicarse oca-sionalmente a diariamente. Conclusiones: El AU urinario está aumentado en individuos con SD. El AU urinario no varía significativamente con el sexo. La práctica diaria de ejercicio físico con intensidad mo-derada reduce la excreción urinaria de AU en el SD.


Physical exercise and urinary uric acid levels in Down’s syndrome 5

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 anoma-ly, 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 Coun-cil Biological Research Centre (Departamento de Medicina Celular y Molecular del Centro de Investigaciones Biológi-cas del Consejo Superior de Investigaciones Científicas [CSIC]). As well as this urine specimen, a questionnaire was completed that included sociodemographic data, perform-ing of physical exercise, and dietary habits. The performing of this study was approved by the CSIC Bioethics Commit-tee. All the participants in the study, or their legal repre-sentatives, 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) deter-mined by the Jaffé 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 deter-mined 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. Sig-nificant differences were considered with a P<.05.

Results

The urine UA levels referenced to Cr were significantly higher in individuals with DS than in the control group, P<.01) (fig.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 significantly 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 (fig. 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 occa-sionally to daily (fig. 3).

No significant variations were observed in the urinary UA excretion with diet, although a higher consumption of cer-tain 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

450

400

350

300

250

200

150

100

50

0Control DS

UA

/ C

r (m

mo

l/mo

l)

*

Figure 1 Comparison of the uric acid/Creatinine (UA/Cr) ratio between the group with SD and the control group. *Indicates significant differences (p<0.01).

700

600

500

400

300

200

100

00 10 20 30

Control DS

40

Age (years)

50 60 70 80

UA

/ C

r (m

mo

l/mo

l)

Figure 2 Changes in the uric acid/Creatinine (UA/Cr) ratio with age. The graph shows second-order polynomial trend lines.

500

400

300

200

100

0OcasionallyWeeklyDaily

UA

/ C

r (m

mo

l/mo

l)

Control DS

Figure 3 Changes in the uric acid/Creatinine (UA/Cr) ratio according to the frequency of performing physical exercise.


6 C. Campos Vaquero et al

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 hyperuricae-mia 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 super-oxide. 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 con-tribute to the increase in UA in DS.

Individuals with DS show a significant increase in mito-chondrial DNA mutations and a reduction in the gene expression of adenosine triphosphatase, an enzyme respon-sible for the biosynthesis of adenosine triphosphate23. The decrease in adenosine triphosphate leads to the accumula-tion of the adenosine deaminase that is deaminated by adenosine monophosphate deaminase into inosine monophosphate, and then converted by inosine 5’-mon-phosphate into inosine, which can enter into the blood and produce hypoxanthine. Xanthine oxidase converts hypoxan-thine 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 Márcia 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 Jeru-salem, observed that, in active males who performed physical exercise, the serum uric acid concentration was significantly lower than in inactive males. They also

obtained an inverse correlation between the serum uric acid concentration and physical activity. Although human cells lack the enzyme uricase that converts UA into allan-toin, 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 practis-ing 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 uri-

nary 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

Down’s 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 conflict of interests.

Acknowledgements

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

References

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2. Lejeune J, Gautier M, Turpin R. Etude des chromosomes somatiques de 9 enfants mongoliens. C.R. Acad Sci Paris. 1959; 248:1721-8.

3. Hassold TJ, Jacobs PA. Trisomy in man. Annu Rev Genet. 1984; 18:69-97.

4. Hook EB. Epidemiology of Down syndrome. In: Pueschel SM, Rynders JE (editors). Down syndrome. Advances in biomedicine and Behavioral Sciences. Cambridge MA: Ware; 1982.

5. Mikkelsen M. Down’s syndrome cytogenetic epidemiology. Hereditas. 1977;86:45-59.

6. Mercer ES, Broecker B, Smith EA, Kirsch AJ, Scherz HC, Massad CA. Urological manifestations of Down’s syndrome. J Urol. 2004;171:1250-3.

7. Málaga S, Pardo R, Málaga I, Orejas G, Fernández-Toral J. Renal involvement in Down’s syndrome. Pediatr Nephrol. 2005;20: 614-7.

8. Guzmán R, Campos C, López-Fernández E, Casado A. Biomarkers of age effect on renal function in Down’s syndrome. Biomarkers, 2011:16:679-85.

9. Wisniewski K, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol. 1985;17:278-82.

10. Barr DB, Wilder LC, Caudill SP, González AJ, Needham LL, Pikle JL. Urinary creatinine concentrations in the U.S. population: Implications for urinary biologic monitoring measurements. Environ Health Perspect. 2005;113:192-200.

11. Watt JL, Stephen GS. Linphocyte culture for chromosome analysis. En: Human Citogenetic, a practical approach. Oxford England: IRI. Press LTD; 1986.

12. Duncan PH, Gochman N, Cooper T, Smith E, Bayse D. A candidate reference method for uric acid in serum. I. Optimization and evaluation. Clin Chem. 1982;28:284-90.

13. Jaffé M. Über den Niederschlang, welchen Pikrinsäure in normalen Harn erzeugt und über eine neue Reaktion des Kreatinins. Z Physiol Res Chem. 1986;10:391-400.

14. Varley H, Gowenlock AH, Bell M. Practical Clinical Biochemistry. vol. 1. 5th ed. London: Heinemann Medical Books; 1980.

15. Sorensen LF. The elimination of uric acid in man studied by means of C14 labelled uric acid. Scan J Clin Invest. 1960;12 (Supp 54):1-214.

16. Leathes JB. On diurnal and nocturnal variations in the excretion of uric acid J Physiol. 1906;35:125-30.

17. Coburn SP, Sirlin EM, Mertz ET. Metabolism of N15 labeled uric acid in Down’s syndrome. Metabolism. 1968;17:560-2.

18. Ciompi ML, Bazzichi LM, Bertolucci D, Mazzoni MR, Barbieri P, Mencacci S, et al. Uric acid metabolism in two patients with coexistent Down’s syndrome and gout. Clin Rheumatol. 1984; 3:229-33.

19. Nagyová A, Sustrová M, Raslová K. Serum lipid resistance to oxidation and uric acid levels in subjects with Down’s syndrome. Physiol Res. 2000;49:227-31.

20. Zitnanová I, Korytár P, Aruoma OI, Sustrová M, Garaiová I, Muchová J, et al. Uric acid and allantoin levels in Down’s 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 Down’s 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 Down’s 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 Down’s 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 fluids. 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 Reye’s syndrome. Arch Biochem Biophys. 1987;253:91-6.




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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

KEYWORDSTrisomy 21;Aneoploidy;Nondisjunction;Maternal age;Down syndrome

AbstractBackground: Down’s 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 find 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 mother’s of <35 years and less than twenty percent to mother’s age >35 years. DS cases born to mother’s of age less than 30 years were 69.5%. Mean age of mother was 29.5 years. Partial correlation coefficient between mother’s 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: [email protected] (Neelkamal).

03_ORIGINAL_ingl_1_2013 (8-12).indd 8 11/04/13 13:09

Maternal age: a controversial factor in trisomy 21 9

Introduction

Down’s 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 Down’s 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

first meiotic division in the ovum4. Several theories have been proposed to explain the increased incidences of Down’s syndrome with advanced maternal age. Another hypothesis proposes that structural, hormonal and immu-nologic 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 rela-tionship 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 Down’s syndrome and in human cytogenetics.

Material and methods

Present study has been conducted on 200 cases of Down’s 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 Down’s syndrome patients were taken. Down’s syndrome cases were subjected to detailed morphological and cytogenetic analysis.

PALABRAS CLAVETrisomía 21;Aneuploidía;No disyunción;Edad materna;Síndrome de Down

Edad materna: un factor de controversia en la trisomía 21

ResumenAntecedentes: El síndrome de Down (SD) es la aneuploidía autosómica más frecuente en humanos. Se caracteriza por un fenotipo complejo que incluye rasgos faciales caracterís-ticos y una apariencia esquelética; constituye la malformación congénita/síndrome de retraso mental más diagnosticado. Aunque la edad avanzada de la madre es un factor de riesgo bien establecido para la etiología del SD, sigue habiendo opiniones contrapuestas al respecto.Objetivo: El estudio se llevó a cabo para descubrir el efecto de la edad materna en la etiología de la trisomía 21.Material y métodos: Este estudio se realizó contemplando casos de SD de diferentes ba-rrios del estado de Haryana (India). Los casos de SD estaban sujetos a un análisis morfo-lógico y citogenético detallado.Resultados: En este estudio, más del 80% de los niños con SD habían nacido de madres jóvenes, de < 35 años, y menos del 20%, de madres de > 35 años. Los casos de SD nacidos de madres con edades inferiores a 30 años supusieron el 69,5%. La media de edad de la madre eran 29,5 años. El coeficiente de correlación parcial entre la edad de la madre y el número de casos de SD (manteniendo constante la edad del padre) se calculó como r = 0,315.Conclusión: El resultado de este estudio no es favorable al efecto de la edad materna avanzada en la incidencia de niños 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 (genéticos y ambientales) que afecten la formación de un cigoto trisómico. Es necesario realizar más estudios para investigar los diferentes factores que regulan la segregación y la recombinación en humanos.


10 M. Vashist and Neelkamal

Results

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

In case of free trisomy, mother’s age at pregnancy was between 20-40 years. In the case of translocation and

mosaicism the mother’s 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%) mother’s age was between 26-30 years (table 4). Present study sup-

25

20

15

10

5

0

Age (years)

< 20

20-2

223

-25

26-2

829

-31

32-3

435

-37

38-4

0>

40

Freq

uen

cy (

%)

Figure 1 Percentage frequency of maternal age in Down’s syndrome patients.

< 30> 30

Figure 2 Percentage frequency of Down’s syndrome cases having mother’s age <30 and >30.

Table 2 Maternal age in cytogenetically analysed cases

N.ºCytogenetics of Down’s syndrome cases

N.º of cases (%)

Age of mother (years)

1 Free trisomy 21 94.5 20-40

2 Translocation 14; 21 1.1 28

3 Mosaic for translocation 21; 21

1.1 32

4 Mosaic for free trisomy 21

1.1 34

5 Normal cytogenetics with Down’s syndrome phenotype

2.2 25-28

Table 3 Cytogenetics of Down’s syndrome cases and maternal age (<30 years and >30 years)

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 Down’s syndrome phenotype

1.1 1.1

Total (69.5%) (30.5%)

Table 1 Distribution of maternal age in Down’s syndrome (D.S.) & Control cases (n=200)

Age range (years)

N.º of mothers Percentage

SD Control SD Control

< 20 9 15 4.5

69.5

7.5

86.021-25 60 71 30.0 35.5

26-30 70 86 35.0 43.0

31-35 27 16 13.530.5

8.014.0

> 35 34 12 17.0 6.0

Total 200 200


Maternal age: a controversial factor in trisomy 21 11

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 insignificant in the etiology of Down’s 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 Down’s syndrome patients in the present study depicted that mean maternal age was 29.5 years for Down’s syndrome cases. In the western studies the mean maternal age at the conception of Down’s syndrome children was found to be 34.4 years12. There must be other factors playing role in birth of Down’s 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 Down’s syndrome13.

Present study reveals that more than 80% of Down’s syn-drome children were born to young mother’s of <35 years and less than 20% born to mother’s 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 Down’s syn-drome child. Therefore Shuttleworth explanation does not provide answer to the cases where Down’s syndrome child is born to a young mother. It has recently been shown that 95% of cases of trisomy 21 appear to result from nondis-junction occurring in the 1st meiotic division on the ovum16. Along with the advanced maternal age, altered recombina-

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 nondisjunc-tion18. The compromised microcirculation hypothesis explains the occurrence of aneuploidy in primary and sec-ondary oocytes, sperm precursor cells, tumor and embry-onic cells. It also explains why women of all reproductive ages may have a Down’s syndrome child19. It was also sug-gested 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 Down’s 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 hypoth-esis involving hormonal imbalance. A multidisciplinary approach to know the trisomy induction and influence of maternal age is required. Molecular approaches to the clas-sical ones of biochemistry, cell biology, cytogenetics, epi-demiology, 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 4 Maternal age in free trisomy 21 cases

Mother’s age (years)Down’s syndrome cases (%)

< 20 (4.9)

21-25 (12.2)(67.3)*

26-30 (50.2)

31-35 (20.1) (27.2)**

36-40 (7.1)

> 40 —

*Age below 30.**Age above 30.

Table 5 Maternal age and the percentage of Down’s syndrome (DS) cases in India

Age range (years)

DS in other parts of India (%)

DS in present study (%)

Controls (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


12 M. Vashist and Neelkamal

Funding

Funded by UGC.

��

Authors declare not to have any conflict 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.

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. Influence 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.




www.fcsd.org



CASE REPORT

Unusual cause of respiratory distress: Morgagni hernia associated to Down’s 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

KEYWORDSMorgagni hernia;Down’s syndrome;Respiratory distress

AbstractMorgagni hernia (MH) is a rare diaphragmatic hernia with 2% rate of congenital diaphragmatic hernias. Is reported Down’s 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.

* Correspondence author.E-mail: [email protected] (S. Degerli).

PALABRAS CLAVEHernia de Morgagni;Síndrome de Down;Dificultad respiratoria

��de Down

ResumenLa hernia de Morgagni (HM) es una hernia diafragmática poco frecuente, con un índice de hernias diafragmáticas congénitas del 2%. El síndrome de Down (SD) es la anomalía cro-mosómica más frecuente notificada. Desde el punto de vista clínico, hay una variación muy amplia entre individuos por sus rasgos característicos y las malformaciones sistémi-cas asociadas. La coexistencia de hernia de Morgagni y síndrome de Down se ha notifica-do en aproximadamente un 20%.En el servicio de urgencias se ingresó a una mujer con SD para evaluar una neumonía recurrente acompañada de fiebre y tos seca persistente. En este caso, se observó que la anomalía radiográfica era en realidad HM, con asas intestinales en el lado derecho del tórax. Presentamos este caso para dejar constancia de una asociación asintomática entre el SD y la HM.

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. It’s 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 Down’s 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 infiltrative radio opacity consistent with pneumonia (fig. 1). The left lung was out of pathology.

Thorax computerized tomography confirmed the diagno-ses of intestinal herniation through diaphragm and infiltra-tion. 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.

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 fol-lowed 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 her-nia (DH) and possibility of rapid clinical deterioration. Patient was started on oxygen therapy and closely moni-tored. 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 it’s 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 reflects the importance of genetics as an etiologic factor. DH’s 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 1 Intestinal loops are seen in the right thorax on chest x-ray.

Figure 2 The diagnosis is confirmed with CT.

04_CASO_ingl_1_2013 (13-15).indd 14 11/04/13 13:09

Unusual cause of respiratory distress: Morgagni hernia associated to Down’s syndrome 15

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 asso-ciation presenting with respiratory distress have been reported but different from other cases, our patient need-ed further ICU follow up and invasive respiratory sup-port9,10.

Hernia diagnosis is made with chest x-ray and visualiza-tion 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 Down’s syndrome can have different anomalies and recurrent pneumonia, dyspeptic complaints and especially life threatening respiratory distress may be the only symptoms of MH.

References

1. Harrison MR, Bjordal RI, Langmark F, Knutrud O. Congenital diaphragmatic hernia: the hidden mortality. J Pediatr Surg. 1978;13:227.

2. Sweed Y, Puri P. Congenital diaphragmatic hernia: influence of associated malformations on survival. Arch Dis Child. 1993;69 (1 Spec No):68.

3. Al-Salem AH, Khawaher HA. Delayed presentation of bilateral Morgagni’s hernia in a child with Down’s syndrome. Saudi Med J. 2002;23:237-9.

4. Kubiak R, Platen C, Schmid E, Gruber R, Ludwig K, Rauh W. Delayed appearance of bilateral Morgagni hernia in a child with Down’s syndrome. Pediatr Surg Int. 1998;13:600-1.

5. Picard E, Bennun A, Fisher D, Schwartz S, Goldberg M, Goldberg S. Morgagni hernia mimicking pneumonia in Down’s syndrome. J Pediatr Surg. 2007;42:1608-11.

6. Jetley NK, Al-Assiri AH, Al-Helal AS, Al-Bin Ali AM. Down’s syndrome as a factor in the diagnosis, management, and outcome in patients of Morgagni hernia. J Pediatr Surg. 2011; 46:636-9.

7. Slavotinek AM. The genetics of congenital diaphragmatic hernia. Semin Perinatol. 2005;29:77.

8. Hedrick HL, Crombleholme TM, Flake AW, Nance ML, von Allmen D, Howell LJ, et al. Right congenital diaphragmatic hernia: Prenatal assessment and outcome. J Pediatr Surg. 2004;39:319.

9. Beg MH, Rashidi ME, Jain V. Morgagni hernia with Down syndrome: a rare association. Indian J Chest Dis Allied Sci. 2010;52:115-7.

10. Nguyen T, Eubanks PJ, Nguyen D, Klein SR. The laparoscopic approach for repair of Morgagni hernias. JSLS. 1998;2:85-8.

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