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This is the most common serious disorder of the autosomal chromosomes. The overall incidence in the United States is 1 in 700 live births. Most cases result from an extra copy of the long arm region of q22.1 to q22.3 on chromosome 21, resulting in a trisomy 21. In 95% of cases of Trisomy 21, the extra chromosome is of maternal origin. It results from meiotic nondisjunction but the reason for this is still unknown. In a smaller percentage, there are a normal number of chromosomes (46) but extra chromosomal material is present as a translocation, such as a Robertsonian translocation. In these cases, the translocated chromosome is inherited from one of the parents, usually the mother. The fertilized egg has two copies of chromosome 21 and the extra translocated material acts as a triple gene dosage. Mosaics result form mitotic nondisjunction of chromosome 21 during an early stage.


Epidemiology Maternal Age
Disease Associations

Immune System

Pathogenesis Chromosomal changes
Robertsonian Translocation
Gross Appearance and Clinical Variants  
Histopathological Features and Variants Transient Abnormal Myelopoiesis
Laboratory/Radiologic/Other Diagnostic Testing

Nuchal Thickness
Triple Test

Prognosis Functional Status
Growth Curves
Life Expectancy
Treatment Donepezil
Commonly Used Terms  
Internet Links  


MATERNAL AGE Maternal age is a well-known risk factor for DS. It must be remembered that this risk is for cases of trisomy 21 and not for mosaics or translocations
<20 yrs
35 yrs
40 yrs
>45 yrs

Preference assessment of prenatal diagnosis for Down syndrome: is 35 years a rational cutoff?

Grobman WA, Dooley SL, Welshman EE, Pergament E, Calhoun EA.

Sections of Maternal-Fetal Medicine and Reproductive Genetics, Northwestern University Medical School Institute for Social Research and Health Policy Studies, Northwestern University, Chicago, Illinois.

Prenat Diagn 2002 Dec;22(13):1195-200 Abstract quote

OBJECTIVE: To compare the perceptions of miscarriage and birth of a child with Down syndrome among pregnant women and to evaluate the implications of these preferences for the traditional 35-year old maternal age risk boundary.

METHODS: An interviewer-administered survey was given to 186 pregnant women receiving antepartum care at a university hospital. Preferences, as reflected by utilities, for birth of a child with Down syndrome and pregnancy miscarriage, stratified by patient characteristics, were assessed.

RESULTS: The utility for the birth of a child with Down syndrome decreased (p < 0.001) as clinical severity increased from mild (0.78) to severe (0.65). Miscarriage of a pregnancy had a mean utility of 0.76 +/- 0.31. Women who desired prenatal diagnosis had a utility value for miscarriage (0.79 +/- 0.28) that was significantly higher than for the birth of a child with Down syndrome of unknown severity (0.73 +/- 0.27). In multivariable logistic regression, desire for prenatal diagnosis was the only factor associated with a preference of miscarriage over birth of an affected child (odds ratio 2.26, 95% confidence interval 1.03, 4.96).

CONCLUSION: Women who desire prenatal diagnosis do not perceive the birth of a child with Down syndrome and a pregnancy miscarriage to be equivalent health states. This finding calls into question the rationale of the 35-year-old maternal age criterion and suggests that actual patient preferences should be better incorporated into the decision to offer definitive prenatal diagnosis.



Intraneuronal A-Amyloid Precedes Development of Amyloid Plaques in Down Syndrome

Kymberly A. Gyure, etal.

Arch Pathol Lab Med 2001;125:489–492 Abstract quote

Context.—Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes.

Objective.—To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome.

Methods.—Histologic and immunocytochemical study of a series of autopsy brains (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital.

Results.—The principal observations included the presence of intraneuronal A immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of A) and the formation of senile plaques and neurofibrillary tangles.

Conclusions.—We propose the following sequence of events in the development of neuropathologic changes of Alzheimer disease in Down syndrome: (1) intracellular accumulation of A in neurons and astrocytes, (2) deposition of extracellular A and formation of diffuse plaques, and (3) development of neuritic plaques and neurofibrillary tangles with activation of microglial cells.


Immunological features of Down's syndrome: a review.

Nespoli L, Burgio GR, Ugazio AG, Maccario R.

Department of Pediatrics, University of Pavia, Italy.


J Intellect Disabil Res 1993 Dec;37 ( Pt 6):543-51 Abstract quote

Young patients with Down's syndrome (DS) have high rates of infections, malignancies and autoimmune phenomena. Therefore, DS may be considered as a model of precocious, abnormal ageing of the thymus-dependent system in man. In DS children less than 6 years of age, the levels of serum immunoglobulins did not differ from healthy controls, but after that age, considerable hyper-IgG and -IgA were found. Furthermore, high levels of IgG1 and IgG3 have been found, whereas a progressive decline of IgG2 and IgG4 with age has been observed. The frequency of hepatitis B virus carriers even in the youngest age group is much higher among DS children. It has been reported that an IgG response was detectable in 75% of controls after HBsAg vaccination as compared to the 16.6% of DS patients.

The presence of autoantibodies against human thyroglobulin did show a positive association with HB Virus Ag carriers, but only in the oldest DS subjects. Natural antibodies against intestinal antigens are low, while in the presence of cow's milk, abnormally high titres against casein and beta-lactoglobulin were present. High levels of IgG antibodies against gliadin have been observed. In spite of a normal percentage of CD3- and CD2-positive lymphocytes, a high proportion of cells express low-avidity receptors for sheep erythrocytes. Although the proportion of CD4+ T-lymphocyte helper-cells is normal, a marked imbalance in the CD4+ subpopulations has been documented. The percentage of suppressor-cytotoxic CD8+ lymphocytes is markedly increased. The responses to phytohemagglutinin and concanavalin A are within the normal range in the first decade of life and decline progressively thereafter.

A recent study reported defective proliferative response to allo-mixed lymphocyte culture, with decreased expression of the membrane CD25, low secretion of interleukin 2 in the supernatant and depressed allo-specific cytotoxic activity.


Down syndrome, transient myeloproliferative disorder, and infantile liver fibrosis.

Schwab M, Niemeyer C, Schwarzer U.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

Med Pediatr Oncol 1998 Sep;31(3):159-65 Abstract quote

BACKGROUND: In neonates, Down syndrome is rarely accompanied by the leukemoid reaction called transient myeloproliferative disorder.

PROCEDURES AND RESULTS: We present clinical and histopathologic data of another Down syndrome neonate with transient myeloproliferative disorder and severe infantile liver fibrosis. These findings in our patients are compared in detail with the 20 cases published previously. Similar clinical and laboratory findings were present in all 21.

CONCLUSIONS: Knowing the cellular mechanism of hepatic fibrosis and its modulation by growth factors (e.g, platelet-derived growth factor), a pathogenetic link between transient myeloproliferative disorder and the development of liver fibrosis in Down syndrome neonates seems probable. An association of this triad of findings no longer appears to be accidental.

Fetal megakaryocytic dyshemopoiesis in Down syndrome: association with hepatic and pancreatic fibrosis.

Becroft DM.

Department of Pathology, University of Auckland, New Zealand.

Pediatr Pathol 1993 Nov-Dec;13(6):811-20 Abstract quote

Trisomy 21 was diagnosed by prenatal blood sampling at 30 and 31 weeks of gestation, respectively, in two fetuses with hepatosplenomegaly. In both, the fetal blood contained blast cells and cells showing megakaryocytic differentiation. Case 1 died neonatally 1 week later and the cellular infiltration causing enlargement of liver and spleen had a megakaryocytic/megakaryoblastic component staining positively for von Willebrand factor and binding to Ulex europaeus 1. Case 2, when stillborn 4 weeks later, had remarkably severe hepatic and pancreatic fibrosis. Cells in pulmonary vessels had morphology and immunohistochemical reactions consistent with megakaryocytic/megakaryoblastic differentiation.

Comparison of the two cases suggests that the visceral fibrosis of perinatal Down syndrome may progress very rapidly in utero. They demonstrate further the association of the fibrosis with a dyshemopoiesis in which there is proliferation of cells of megakaryocytic lineage and a close relationship to the transient leukemia of neonatal Down syndrome.

Unusual diffuse liver fibrosis accompanying transient myeloproliferative disorder in Down's syndrome: a report of four autopsy cases and proposal of a hypothesis.

Miyauchi J, Ito Y, Kawano T, Tsunematsu Y, Shimizu K.

Division of Pathology, National Children's Hospital, Tokyo, Japan.

Blood 1992 Sep 15;80(6):1521-7 Abstract quote

Transient myeloproliferative disorder (TMD), an acute leukemia-like disorder in neonates with Down's syndrome, is characterized by spontaneous regression of abnormal blast growth. Because proliferating blasts frequently express phenotypes of megakaryocytic lineage and, as a result, this disorder resembles acute megakaryoblastic leukemia (AMKL), it would be of interest to determine whether myelofibrosis, a common complication of AMKL, is also present in TMD.

Pathologic observations of four autopsy cases of TMD showed that myelofibrosis was not present in any of them, whereas intralobular diffuse liver fibrosis was present in all of them. Laboratory data of four additional cases showed hepatic dysfunction in all of them, suggesting a close association between hepatic lesions and TMD.

From these results, we propose a hypothesis that the abnormal blasts with megakaryocytic properties in TMD originate from the fetal liver and cause liver fibrosis, as AMKL cells are thought to cause myelofibrosis by producing collagen-stimulating cytokines in the bone marrow. This hypothesis also seems to explain some other unique aspects of TMD.

Transient abnormal myelopoiesis accompanied by hepatic fibrosis in two infants with Down syndrome.

Yagihashi N, Watanabe K, Yagihashi S.

Department of Pathology, Hirosaki University School of Medicine, Japan.

J Clin Pathol 1995 Oct;48(10):973-5 Abstract quote

Two necropsy cases of Down syndrome are reported. These showed transient abnormal myelopoiesis accompanying characteristic hepatic sinusoidal fibrosis. Numerous megakaryocytes were found in the liver of one case, but not in the other.

Only eight cases of Down syndrome with simultaneous occurrence of hepatic fibrosis and transient abnormal myelopoiesis have been reported.

The cases described here showed slight fibrotic changes in the hyperplastic bone marrow, which were not found in the previously reported cases of transient abnormal myelopoiesis.


Musculoskeletal problems in Down Syndrome European Paediatric Orthopaedic Society Survey: the Israeli sample.

Merrick J, Ezra E, Josef B, Hendel D, Steinberg DM, Wientroub S.

Division for the Mentally Retarded, Ministry of Labor and Social Affairs, State of Israel, Jerusalem, Israel.

J Pediatr Orthop B 2000 Jun;9(3):185-92 Abstract quote

An Israeli sample of 475 individuals representing the full spectrum of those with Down syndrome in the Jewish population is presented.

The sample is part of a European multicenter study evaluating musculoskeletal disorders. Generalized joint laxity was found to have significant relationships with a number of medical conditions (knee problems, patello-femoral instability, genu valgus, pes planus, heart defects, and gastrointestinal problems). Body mass index was also related to feet problems, vertical talus, spinal problems, genu valgum, pes planus, and heart problems.

Yearly multidisciplinary clinical follow-up is recommended in persons with Down syndrome.


Otolaryngologic manifestations of Down syndrome.

Kanamori G, Witter M, Brown J, Williams-Smith L.

Department of Otolaryngology, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA.

Otolaryngol Clin North Am 2000 Dec;33(6):1285-92 Abstract quote

The DS patient has clear anatomic differences in the head and neck region when compared with the general population.

These anomalies include a flat occiput, oblique palpebral fissures, epicanthal folds, speckled irides, a protruding tongue, prominent malformed ears, and a flat nasal bridge. Congenital otologic anomalies and acquired conditions such as otitis media are also more frequently observed in the DS population.

The DS patient is predisposed to obstructive sleep apnea, and the diagnosis of sleep apnea in DS patients is more likely to be delayed. A child with DS who has a narrowed nasopharynx, large tongue, and a subglottis which is smaller than normal must be given special consideration at the time of intubation. Such a patient requires an endotracheal tube two sizes smaller than the standard size appropriate for the patient's age.

The child should also be suspected of having and be evaluated for obstructive sleep apnea, to ensure that appropriate precautions are taken in the perioperative period. Finally, any DS patient undergoing preoperative evaluation for a general anesthetic should have a careful assessment of the cervical spine to avoid dislocation or spinal cord injury. Hearing loss may be suspected in any congenital syndrome. In DS, there is a clearly increased incidence of congenital temporal bone anomalies, external auditory canal stenosis, and otitis media.

All DS patients should undergo hearing assessment in the neonatal period, with follow-up as appropriate. Aggressive treatment of conductive hearing loss and early amplification may be necessary to maximize speech and language development.


Dermatological manifestations of Down's syndrome.

Barankin B, Guenther L.

The University of Western Ontario, 835 Richmond Street, London, Ontario, Canada N6A 3H7.

J Cutan Med Surg 2001 Jul-Aug;5(4):289-93 Abstract quote

BACKGROUND: Down's syndrome (DS) is an extensively researched congenital condition characterized by mental retardation and distinct physical features. The cutaneous manifestations of DS are numerous, yet they seldom receive appropriate attention.

OBJECTIVE: To review the dermatological conditions associated with DS.

METHODS: A review of the medical literature.

RESULTS: DS is associated with an increased incidence of numerous dermatological conditions, some of which may be related to an immunological deficiency.

CONCLUSION: Along with the importance of understanding the physical and psychosocial aspects of DS, an appreciation of the dermatological manifestations of this condition is integral to comprehensive medical care.

Dermatological manifestations of 71 Down syndrome children admitted to a clinical genetics unit.

Ercis M, Balci S, Atakan N.

Department of Pediatrics, Ankara, Turkey.

Clin Genet 1996 Nov;50(5):317-20 Abstract quote

Seventy-one children with Down syndrome who were admitted consecutively to Hacettepe University Children's Hospital Genetics department were examined for skin disorders. None of the patients suffered directly from skin disorders. All were living with their families and had approximately similar living conditions.

\There were 29 children with palmoplantar hyperkeratosis (40.8%), seven with xerosis (9.8%), 22 with seborrheic dermatitis (30.9%), 14 with fissured tongue (20%), eight with geographic tongue (11.2%), and nine with cutis marmorata (12.6%). Nine had normal skin findings. Since palmoplantar hyperkeratosis may be a result of vitamin A deficiency, the serum vitamin A levels of these patients were evaluated.

There was no statistical difference between vitamin A levels of the children with Down syndrome and the control group.


Trisomy 21
47, XX, +21 (female)
46, XX,der(14;21)(q10;q10),+21 (female)

Annotation of human chromosome 21 for relevance to Down syndrome: gene structure and expression analysis.

Gardiner K, Slavov D, Bechtel L, Davisson M.

Eleanor Roosevelt Institute, 1899 Gaylord Street, Denver, CO 80206, USA.

Genomics 2002 Jun;79(6):833-43 Abstract quote

Down syndrome is caused by an extra copy of human chromosome 21 and the resultant dosage-related overexpression of genes contained within it.

To efficiently direct experiments to determine specific gene-phenotype correlations, it is necessary to identify all genes within 21q and assess their functional associations and expression patterns. Analysis of the complete finished sequence of 21q resulted in annotated 225 genes and gene models, most of which were incomplete and/or had little or no experimental verification.

Here we correct or complete the genomic structures of 16 genes, 4 of which were not reported in the annotation of the complete sequence. Our data include the identification of six genes encoding short or ambiguous open reading frames; the identification of three cases in which alternative splicing produces two structurally unrelated protein sequences; and the identification of six genes encoding proteins with functional motifs, two genes with unusually low similarity to their orthologous mouse proteins, and four genes with significant conservation in Drosophila melanogaster.

We further demonstrate that an additional nine gene models represent bona fide transcripts and develop expression patterns for these genes plus nine additional novel chromosome 21 genes and four paralogous genes mapping elsewhere in the human genome.

These data have implications for generating complete transcript maps of chromosome 21 and for the entire human genome, and for defining expression abnormalities in Down syndrome and mouse models.


Cytogenetic and epidemiological findings in Down syndrome, England and Wales 1989 to 1993. National Down Syndrome Cytogenetic Register and the Association of Clinical Cytogeneticists.

Mutton D, Alberman E, Hook EB.

Wolfson Institute of Preventive Medicine, Medical College of St Bartholomew's Hospital, London.


J Med Genet 1996 May;33(5):387-94 Abstract quote

Data from the National Down Syndrome Cytogenetic Register is used to describe the cytogenetics and epidemiology of registered cases. The register comprises notifications from cytogenetics laboratories in England and Wales.

This report is of 5737 cases registered between 1989 and 1993: 2169 prenatal and 3436 postnatal diagnoses, and 132 spontaneous abortions. Eighty eight registrations were from multiple pregnancies. Ninety five percent had regular trisomy 21. In 4% there was a translocation, mostly Robertsonian t(14;21) or t(21;21). One percent were mosaics with one normal cell line. Mean maternal age was raised in free trisomy 21, but not in translocations.

Where families had been investigated, about a third of translocations were inherited, six to seven times more often from the mother than the father. Associations between free trisomy 21 and structural chromosomal defects in the births were no more common than expected from newborn series.

The overall sex ratio was raised (male to female: 1.23 to 1), and there was an excess of associated male sex chromosomal aneuploidy. However, in mosaics with one normal cell line the male to female ratio was 0.8 to 1, and in twins discordant for trisomy 21 there was also a female excess.


Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB induced potassium current.

Neuroscience Graduate Program, USUHS, Bethesda, Maryland, United States.

J Neurophysiol. 2006 Nov 8; [Epub ahead of print] Abstract quote

Down syndrome (DS) is the most common nonheritable cause of mental retardation. DS is the result of the presence of an extra chromosome 21 and its phenotype may be a consequence of overexpressed genes from that chromosome. One such gene is Kcnj6/Girk2, which encodes the G-protein coupled inward rectifying potassium channel subunit 2 (GIRK2). We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus.

Here, we report that this overexpression leads to a significant increase (~2 fold) in GABAB-mediated GIRK current in primary cultured hippocampal neurons. The dose response curves for peak and steady state GIRK current density is significantly shifted left towards lower concentrations of baclofen in Ts65Dn neurons compared to diploid controls, consistent with increased functional expression of GIRK channels. Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single channel conductance compared to diploid. However, significant increases in GIRK channel density was found in Ts65Dn neurons. In normalized baclofen-induced GIRK current and GIRK current kinetics no difference was found between diploid and Ts65Dn neurons, which suggest unimpaired mechanisms of interaction between GIRK channel and GABAB receptor.

These results indicate that increased expression of GIRK2 containing channels have functional consequences which likely affect the balance between excitatory and inhibitory neuronal transmission.
Altered signaling pathways underlying abnormal hippocampal synaptic plasticity in the Ts65Dn mouse model of Down syndrome.

Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, F Edward Herbert School, Bethesda, Maryland 20814, USA.


J Neurochem. 2006 Aug;98(4):1266-77. Abstract quote

The Ts65Dn mouse model of Down syndrome (DS) has an extra segment of chromosome (Chr.) 16 exhibits abnormal behavior, synaptic plasticity and altered function of several signaling molecules. We have further investigated signaling pathways that may be responsible for the impaired hippocampal plasticity in the Ts65Dn mouse.

Here we report that calcium/calmodulin-dependent protein kinase II (CaMKII), phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulated kinase (ERK), protein kinase A (PKA) and protein kinase C (PKC), all of which have been shown to be involved in synaptic plasticity, are altered in the Ts65Dn hippocampus.

We found that the phosphorylation of CaMKII and protein kinase Akt was increased, whereas ERK was decreased. Activities of PKA and PKC were decreased. Furthermore, abnormal PKC activity and an absence of the increase in Akt phosphorylation were demonstrated in the Ts65Dn hippocampus after high-frequency stimulation that induces long-term potentiation.

Our findings suggest that abnormal synaptic plasticity in the Ts65Dn hippocampus is the result of compensatory alterations involving the glutamate receptor subunit GluR1 in either one or more of these signaling cascades caused by the expression of genes located on the extra segment of Chr. 16.

Preimplantation genetic diagnosis for couples at high risk of Down syndrome pregnancy owing to parental translocation or mosaicism.

Conn CM, Cozzi J, Harper JC, Winston RM, Delhanty JD.

The Galton Laboratory, University College London, UK.


J Med Genet 1999 Jan;36(1):45-50 Abstract quote

The population risk for trisomy 21 is 1 in 700 births but some couples are at a much higher risk owing to parental translocation or mosaicism.

We report on the first attempt to carry out preimplantation genetic diagnosis for two such couples using cleavage stage embryo biopsy and dual colour FISH analysis. Each couple underwent two treatment cycles. Couple 1 (suspected gonadal mosaicism for trisomy 21) had two embryos normal for chromosome 21 transferred, but no pregnancy resulted; 64% (7/11) unfertilised oocytes/embryos showed chromosome 21 aneuploidy. Couple 2 (46,XX,t(6;21)(q13;q22.3)) had a single embryo transferred resulting in a biochemical pregnancy; 91% (10/11) oocytes/embryos showed chromosome 21 imbalance, most resulting from 3:1 segregation of this translocation at gametogenesis.

The opportunity to test embryos before implantation enables the outcome of female meiosis to be studied for the first time and the recurrence risk for a Down syndrome pregnancy to be assessed.



Evaluation of a dimeric inhibin-A assay for assessing fetal Down syndrome: establishment, comparison, and monitoring of median concentrations for normal pregnancies.

Erickson JA, Ashwood ER, Gin CA.

ARUP Institute for Clinical and Experimental Pathology, LLC, Salt Lake City, Utah 84108, USA.
Arch Pathol Lab Med. 2004 Apr;128(4):415-20 Abstract quote.

CONTEXT: Several studies report the role of dimeric inhibin-A in assessing risk for fetal Down syndrome. The majority, however, use the Serotec inhibin-A assay and not the newer Diagnostic Systems Laboratories inhibin-A enzyme-linked immunosorbent assay (ELISA).

OBJECTIVES: To establish normal gestational age day-specific medians, to compare our results against previous studies pertaining to the inhibin-A ELISA, and to evaluate long-term assay performance.

DESIGN: Using the inhibin-A ELISA, 100 specimens were assayed for each completed week of gestation for weeks 15 to 20, 50 specimens for 14 weeks, and 54 specimens for 21 weeks or older. Regressed inhibin-A medians were calculated employing a second-degree polynomial fit of the arithmetic medians. Thereafter, inhibin-A ELISA lot comparisons were performed to evaluate consistency.

RESULTS: Regressed values of 182, 174, 175, 184, 201, and 226 pg/mL resulted for weeks 15 to 20, respectively [pg/mL inhibin-A = 4.1528(gestational age)2 - 136.49(gestational age) + 1294.9]. A comparison with 2 other studies shows our values to be lower overall by 15 +/- 11.4% and 16 +/- 2.6%. However, variability between kit lots was as high as 30%.

CONCLUSIONS: The equation derived provides for the calculation of gestational age day-specific inhibin-A medians for integration into maternal serum screening programs with a subsequent decrease in false-positives expected and observed. Our medians differ considerably from those of other studies, with limited data, using the Diagnostic Systems assay. However, lot changes since the initial analysis have exhibited similar inconsistencies. Therefore, we recommend that others incorporating the assay into their screening programs carefully establish, monitor, and adjust their medians accordingly as a result of potential variations.

Down syndrome risk estimation after normal genetic sonography.

Vintzileos AM, Guzman ER, Smulian JC, Yeo L, Scorza WE, Knuppel RA.

Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School/St Peter's University Hospital, New Brunswick, NJ, USA.

Am J Obstet Gynecol 2002 Nov;187(5):1226-9 Abstract quote

OBJECTIVE: The objective of this study was to determine whether there are any indication-specific variations in risk reduction for fetal Down syndrome after a normal genetic sonogram.

STUDY DESIGN: A second-trimester genetic sonogram was offered to all pregnant women who were at increased risk for fetal Down syndrome (>/=1:274) because of either advanced maternal age (>/=35 years), an abnormal triple screen, or both. Outcome information included the results of genetic amniocentesis (if performed), the results of pediatric assessment, and follow-up after birth. Normal genetic sonography was defined as the absence of all ultrasound aneuploidy markers.

RESULTS: The overall prevalence of fetal Down syndrome in the tested population was 1.41% (53/3,753 pregnancies); however, in the presence of normal genetic sonography, the overall prevalence of fetal Down syndrome was 0.21% (7/3,291 pregnancies). The overall risk reduction for fetal Down syndrome in the presence of normal genetic sonography was 6.64-fold (95% CI, 3.01-14.62); the overall negative likelihood ratio was 0.15 (95% CI, 0.07-0.33). In the presence of normal genetic sonography, the risk for fetal Down syndrome was reduced by 83% in patients with advanced maternal age, 88% in patients with abnormal triple screen, 89% in patients with abnormal triple screen who were <35 years old, and 84% in patients who had both abnormal triple screen and advanced maternal age.

CONCLUSION: There were no significant variations in the risk reduction for fetal Down syndrome in the presence of normal genetic sonography. Regardless of the indication for testing, the likelihood for fetal Down syndrome was reduced by 83% to 89%. This information will be useful in counseling pregnant women who are at high risk for fetal Down syndrome and who prefer to undergo genetic sonography before deciding about genetic amniocentesis.


Measurement of nuchal translucency as a single strategy in trisomy 21 screening: should we use any other marker?

Comas C, Torrents M, Munoz A, Antolin E, Figueras F, Echevarria M.

Fetal Medicine Unit, Department of Obstetrics and Gynecology, Institut Universitari Dexeus, Barcelona, Spain.

Obstet Gynecol 2002 Oct;100(4):648-54 Abstract quote

OBJECTIVE: To evaluate the role of nuchal translucency thickness as a single marker in screening for trisomy 21 at 10-16 weeks' gestation.

METHODS: From December 1996 to October 2001, nuchal translucency was measured in 11,281 consecutive early second trimester fetuses referred to our unit for prenatal care and delivery. Scans were performed by eight experienced ultrasonographers, under strict methodological criteria.

RESULTS: Chromosomal abnormalities were found in 118 cases (52 trisomy 21). Using nuchal translucency greater than the 95th centile as a cut-off, the overall detection rate was 71.2% with a specificity of 95.4%, and a positive predictive value of 14%. In the trisomy 21 selected group, detection rate, specificity, and positive predictive value for nuchal translucency were 92.3%, 95.4%, and 8.5%, respectively. The detection rate of trisomy 21 reached 100% when nuchal translucency was measured between 10 and 14 weeks' gestation, maintaining the same specificity.

CONCLUSION: Early second trimester nuchal translucency measurement can achieve prenatal detection rates of trisomy 21 greater than 95% with a 5% false-positive rate. With a detection rate so high, the benefits of using additional markers may be less than previously considered. Although maternal age, other sonographic or Doppler markers, and maternal serum biochemistry might play a role in prenatal strategies to detect fetal chromosomal abnormalities, the high detection rate of trisomy 21 fetuses using nuchal translucency as a single parameter suggests that early nuchal translucency measurement between 10 and 14 weeks' gestation can be a simple screening strategy for this condition.

Fetal nuchal translucency screening in 12495 pregnancies in Sardinia.

Zoppi MA, Ibba RM, Floris M, Monni G.

Department of Obstetrics and Gynecology, Prenatal and Preimplantation Genetic Diagnosis, Fetal Therapy, Ospedale Microcitemico, Via Jenner, 09125 Cagliari, Italy.

Ultrasound Obstet Gynecol 2001 Dec;18(6):649-51 Abstract quote

OBJECTIVE: To examine the distribution of fetal nuchal translucency thickness in normal and chromosomally abnormal fetuses in Sardinia and to determine the effectiveness of screening by a combination of fetal nuchal translucency and maternal age.

METHODS: Fetal nuchal translucency thickness and crown-rump length were measured at 10-14 weeks of gestation in 12 495 pregnancies. A reference range of fetal nuchal translucency thickness for crown-rump length was determined from the 10 001 singleton pregnancies with known normal pregnancy outcome. The median nuchal translucency thickness for crown-rump length was determined by regression analysis of the calculated median values of nuchal translucency thickness for each 0.1 mm interval in crown-rump length. The proportions of unaffected fetuses and those with trisomy 21 or other chromosomal defects with nuchal translucency thickness > 1.5 and 2.0 multiples of the regressed normal median for crown-rump length were calculated. The distribution of estimated risks based on maternal age and fetal nuchal translucency thickness according to The Fetal Medicine Foundation software were also determined and the sensitivity and false-positive rates were calculated.

RESULTS: In the 10 001 normal pregnancies, the median fetal nuchal translucency thickness increased with crown-rump length (median nuchal translucency thickness = 0.3496 + 0.018 x crown-rump length) (r2 = 0.4411). In the singleton pregnancies, there were 64 fetuses with trisomy 21 and 46 with other chromosomal defects. The fetal nuchal translucency thickness was > 1.5 multiples of the median in 510 (5%) of the normal fetuses, in 52 (81%) of the trisomy 21 fetuses and in 33 (72%) of those with other chromosomal defects. The respective values for nuchal translucency thickness > 2.0 multiples of the median were 195 (2%), 41 (64%) and 32 (70%). In 184 multiple pregnancies, there were four fetuses with chromosomal abnormalities and in three of these the nuchal translucency thickness was > 1.5 multiples of the median. Screening by a combination of maternal age and fetal nuchal translucency thickness with a risk cut-off of 1 in 300 identified 90% of trisomy 21 pregnancies and 85% of all other chromosomal defects for a false-positive rate of 9%.

CONCLUSION: Screening for chromosomal defects by measurement of nuchal translucency thickness identifies 80% of fetuses with trisomy 21 for a false-positive rate of 5%. In our population with a median maternal age of 33 years, screening by a combination of maternal age and fetal nuchal translucency thickness with a risk cut-off of 1 in 300 identified 90% of trisomy 21 pregnancies for a false-positive rate of 9%.

Four years experience of first-trimester nuchal translucency screening for fetal aneuploidies with increasing regional availability.

Wayda K, Kereszturi A, Orvos H, Horvath E, PAl A, Kovacs L, Szabo J.

Department of Medical Genetics, Albert Szent-Gyorgyi Medical and Pharmaceutical Center, University of Szeged, Szeged, Hungary.

Acta Obstet Gynecol Scand 2001 Dec;80(12):1104-9 Abstract quote

BACKGROUND: A prospective screening study was carried out at the regional genetic and perinatal center in South Hungary in order to determine the efficiency of first-trimester nuchal translucency screening for fetal aneuploidies, following augmentation of the availability of nuchal translucency screening in the region by the inclusion of newly-trained hospital sonographers.

METHODS: Nuchal translucency thickness was measured by transvaginal sonography in 7,044 women with singleton or multiple pregnancies at weeks 10-12. Fetal karyotyping was performed when the nuchal translucency was . or = 2.5 mm, and in women with fetuses at high cytogenetic risk.

RESULTS: Follow-up was performed in 6,841 of the 7,044 screened women. An abnormal karyotype was found in 33 cases (0.48%). The level of increased nuchal translucency was 4.5% at a cutoff of > or = 2.5 mm, and 2.8% at a cutoff of > or = 3 mm. Seventeen cases of trisomy 21, eight of trisomy 18, four of trisomy 13, one of 45,X, one of triploidy and two cases with other chromosomal abnormalities were detected. In the 33 fetuses with a chromosomal abnormality, the nuchal translucency thickness was <2.5 mm in a case of trisomy 18, > or = 2.5 mm in 32 cases and > or = 3 mm in 28 cases. With cutoffs of 2.5 mm and 3 mm, the sensitivity was 96.97% and 84.85%, respectively.

CONCLUSIONS: Application of a nuchal translucency thickness cutoff of 2.5 mm is highly efficient for the screening of fetal aneuploidies at 10-12 weeks. This efficiency can be maintained by increasing the regional availability of nuchal translucency screening through the inclusion of newly-trained hospital sonographers.

Screening for trisomy 21 by fetal nuchal translucency and maternal age: a multicenter project in Germany, Austria and Switzerland.

Gasiorek-Wiens A, Tercanli S, Kozlowski P, Kossakiewicz A, Minderer S, Meyberg H, Kamin G, Germer U, Bielicki M, Hackeloer BJ, Sarlay D, Kuhn P, Klapp J, Bahlmann F, Pruggmayer M, Schneider KT, Seefried W, Fritzer E, von Kaisenberg CS; German-Speaking Down Syndrome Screening Group.

Department of Obstetrics and Gynaecology, Kiel University Hospital, Michaelisstrasse 16, 24105 Kiel, Germany.


Ultrasound Obstet Gynecol 2001 Dec;18(6):645-8 Abstract quote

OBJECTIVE: To examine the effectiveness of screening for trisomy 21 by a combination of maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation in Germany, Austria and Switzerland.

METHODS: This was a multicenter study of screening for trisomy 21 by a combination of maternal age and fetal nuchal translucency thickness at 10-14 weeks of gestation. All the sonographers involved in the study had received The Fetal Medicine Foundation Certificate of Competence in the 10-14-week scan. Fetal nuchal translucency thickness and crown-rump length were measured in 23 805 singleton pregnancies with live fetuses. In each case the risk for trisomy 21 was estimated on the basis of maternal age and fetal nuchal translucency thickness for crown-rump length with the use of The Fetal Medicine Foundation's software. The distribution of estimated risk was determined and the sensitivity and false-positive rate for a risk cut-off of 1 in 300 was calculated.

RESULTS: Fetal nuchal translucency thickness was successfully measured in all 23 805 pregnancies and outcome was available in 21 959. The median maternal age was 33 (range 15-49) years and in 7935 (36.1%) the age was 35 years or greater. The median gestation at screening was 12 (10-14) weeks and the median fetal crown-rump length was 61 (range 38-84) mm. The estimated risk for trisomy 21 based on maternal age and fetal nuchal translucency thickness for crown-rump length was 1 in 300 or greater in 13.0% (2800 of 21 475) normal pregnancies, in 87.6% (184 of 210) of those with trisomy 21 and in 87.2% (239 of 274) with other chromosomal defects.

CONCLUSIONS: In Germany, Austria and Switzerland the results of screening for chromosomal defects by measurement of fetal nuchal translucency thickness, in centers with appropriately qualified sonographers and using The Fetal Medicine Foundation's software, are similar to those reported in the UK using the same methodology.

Screening for Down syndrome using first-trimester ultrasound and second-trimester maternal serum markers in a low-risk population: a prospective longitudinal study.

Audibert F, Dommergues M, Benattar C, Taieb J, Thalabard JC, Frydman R.

Department of Obstetrics and Gynecology, Hopital Antoine Beclere, Universite Paris XI, Paris, France.

Ultrasound Obstet Gynecol 2001 Jul;18(1):26-31 Abstract quote

OBJECTIVES: To compare nuchal translucency and second-trimester maternal serum measurements as alternative methods of antenatal screening for Down syndrome in a low-risk population and to evaluate the consequence of combining the results in the estimation of risk.

DESIGN: In a consecutive series of 4130 women aged less than 38 years with a singleton pregnancy, we examined both the detection rate of Down syndrome by nuchal translucency measurement at 10-14 weeks and maternal serum screening by human chorionic gonadotrophin and alpha-fetoprotein at 14-18 weeks. Women with a nuchal translucency measurement of > or = 3 mm and women with a maternal serum screening-derived risk > or = 1/250 were recommended to have amniocentesis. A second-trimester detailed ultrasound scan was also performed in all women. The outcome of all pregnancies was recorded prospectively and the detection rate and false-positive rate of different screening strategies were retrospectively analyzed.

RESULTS: Out of the 4130 pregnancies that were followed (mean maternal age, 30.1 years), 12 cases of Down syndrome were observed (0.28%), all detected prenatally. Seven of 12 cases had a nuchal translucency measurement of > or = 3 mm (58%), and six out of 10 cases with available maternal serum screening had a calculated risk of > or = 1/250 (60%). Four of the five Down syndrome cases with a nuchal translucency measurement of < 3 mm were detected by subsequent maternal serum screening. At a threshold giving 5% of positive tests, the sensitivity of nuchal translucency, maternal serum screening and combined risk screening were 75%, 60% and 90%, respectively.

CONCLUSIONS: In screening for Down syndrome, an approach which combines the results from first-trimester nuchal translucency and second-trimester biochemistry is effective and increases the detection rate compared to the use of any single test. However, this strategy is likely to raise the false-positive rate and the interpretation of maternal serum screening-derived risk should be combined with the first-trimester nuchal translucency measurement.

Critical appraisal of the use of nuchal fold thickness measurements for the prediction of Down syndrome.

Locatelli A, Piccoli MG, Vergani P, Mariani E, Ghidini A, Mariani S, Pezzullo JC.

Divisione di Ostetricia e Ginecologia, Istituto di Scienze Biomediche San Gerardo, Monza, Italy.

Am J Obstet Gynecol 2000 Jan;182(1 Pt 1):192-7 Abstract quote

OBJECTIVE: Nuchal fold thickness is the best ultrasonographic predictor of fetal trisomy 21. However, the risk assigned on the basis of the commonly used threshold of nuchal fold thickness >/=6 mm does not take into consideration the significant associations between nuchal fold thickness and gestational age and between maternal age and Down syndrome. We propose a new method of calculating Down syndrome probability that takes into account both gestational age at examination and previously assessed probability of Down syndrome.

STUDY DESIGN: Nuchal fold thickness was measured at ultrasonographic examination at 14 to 22 weeks' gestation without previous knowledge of the fetal karyotype. Nuchal cystic hygromas were excluded from analysis. Statistical analyses included correlation, logistic regression to control for other ultrasonographic predictors of trisomy 21 and for maternal age, receiver operating characteristic curve, and likelihood ratios (defined as the ratio of the sensitivity to the false-positive rate). P <.05 was considered significant.

RESULTS: Mean gestational age at ultrasonography was 16.9 weeks' gestation (range, 14-22 weeks' gestation). Mean (+/-SD) nuchal fold thickness in fetuses with trisomy 21 (4.7 +/- 1.6 mm; n = 29) was greater than in euploid fetuses (3.2 +/- 0.9; n = 780; P <.001). Logistic regression analysis established that nuchal fold thickness was a significant predictor of trisomy 21 independent both of the other ultrasonographic markers and of maternal age (P <.001). Regression analysis showed that nuchal fold thickness was significantly correlated with gestational age among both fetuses with trisomy 21 and euploid fetuses and that the regression line of fetuses with trisomy 21 had a slope similar to that of euploid fetuses. The difference between observed and expected nuchal fold thicknesses on the basis of the biparietal diameter (as a function of gestational age) was used to obviate the confounding effect of gestational age. Differences between observed and expected nuchal fold thicknesses were then used to calculate likelihood ratios. These likelihood ratios could then be multiplied by the individual prior probability to obtain a patient-specific Down syndrome probability.

CONCLUSION: Nuchal fold thickness is correlated with gestational age in both euploid fetuses and fetuses with Down syndrome. Use of the difference between observed and expected nuchal fold thicknesses to determine likelihood ratios allows the calculation of individual posterior probabilities of Down syndrome that take into consideration both gestational age and maternal age.

Gestational age standardized nuchal thickness values for estimating mid-trimester Down's syndrome risk.

Bahado-Singh RO, Oz UA, Kovanci E, Deren O, Feather M, Hsu CD, Copel JA, Mahoney MJ.

Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.

J Matern Fetal Med 1999 Mar-Apr;8(2):37-43 Abstract quote

OBJECTIVE: Our aim was to develop gestational age standardized indices of fetal nuchal thickening. In addition, we wanted to develop a method for combining nuchal thickness data with maternal age for calculating individual Down's syndrome risk.

METHODS: Nuchal thickness was measured prospectively in pregnancies undergoing genetic amniocentesis. A regression equation for expected median nuchal thickness based on the biparietal diameter (BPD) was developed. Nuchal thickness values were expressed as multiples of the median (MoM). Additionally, a new parameter, percentage increase in nuchal thickness (PIN) (measured minus expected nuchal thickness) X100/expected nuchal thickness, was used. Receiver operator characteristics curves for Down's syndrome detection based on nuchal thickness values expressed as MoM, PIN, and in mm were compared. Log10 transformation of MoM data resulted in a Gaussian distribution, and the Down's syndrome likelihood ratios were calculated based on the heights of the Gaussian curves. Likelihood ratios were also calculated based on PIN values. The screening efficiency of maternal age alone was compared to age plus MoM, and age plus PIN values by multiplying age-related risk by the likelihood ratio corresponding to the given nuchal thickness MoM or PIN values.

RESULTS: There were 3,574 chromosomally normal and 50 Down's syndrome fetuses in the study. Both PIN and MoM values for nuchal thickness were closely correlated (R = 1.00, P<0.001) and each was poorly correlated with gestational age (R = 0.018, P = 0.28). The Down's syndrome screening efficiency of PIN, MoM, and nuchal thickness values in mm were not significantly different. The addition of nuchal thickness data to maternal age-related risk significantly improved the Down's syndrome screening efficiency: Area under the ROC curve for maternal age risk = 0.58, maternal age + PIN area = 0.79 (P<0.001 compared to maternal age alone) and for maternal age + MoM = 0.77 (P<0.005 compared to maternal age alone).

CONCLUSIONS: The development of gestational age standardized nuchal thickness indices makes it possible to combine ultrasound and maternal age-related risk to derive individual Down's syndrome odds.

Screening for Down's syndrome by fetal nuchal translucency measurement in a high-risk population.

Pajkrt E, Mol BW, van Lith JM, Bleker OP, Bilardo CM.

Department of Obstetrics and Gynecology, University of Amsterdam, The Netherlands.


Ultrasound Obstet Gynecol 1998 Sep;12(3):156-62 Abstract quote

OBJECTIVE: To examine the discriminative capacity of nuchal translucency measurement in the detection of trisomy 21 and other chromosomal anomalies.

DESIGN: Prospective cohort study.

SUBJECTS: A total of 2247 women with viable singleton pregnancies between 10 and 14 weeks' gestation attending a prenatal diagnosis center for fetal karyotyping.

METHODS: The fetal nuchal translucency was measured transabdominally in all women before invasive prenatal testing.

RESULTS: Chromosomal abnormalities were found in 63 fetuses, including 36 with Down's syndrome. The likelihood of the presence of chromosomal abnormalities increased with larger nuchal translucency thickness. A nuchal translucency of 3 mm or more identified 25 out of 36 fetuses (69%) with trisomy 21 at the expense of a 4.0% false-positive rate. Correction of nuchal translucency measurements for differences due to variation of the measurement with gestational age, either by using the 'delta-value' or multiples of the median (MoM), did not improve the detection rate in our patient data set.

CONCLUSIONS: The discriminative capacity of nuchal translucency measurement makes it a useful tool in screening for trisomy 21 and other chromosomal anomalies.

Subtle ultrasonographic anomalies: do they improve the Down syndrome detection rate?

Deren O, Mahoney MJ, Copel JA, Bahado-Singh RO.

Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.


Am J Obstet Gynecol 1998 Mar;178(3):441-5 Abstract quote

OBJECTIVE: Our purpose was to determine whether the identification of subtle anomalies further improves Down syndrome detection over standard ultrasonographic biometry and the detection of gross morphologic defects.

STUDY DESIGN: The screening efficiency of clinodactyly, dilated renal pelvis (> or =4 mm), echogenic bowel, mild ventriculomegaly (> or =10 to 15 mm), and two-vessel cord was determined prospectively in midtrimester fetuses at amniocentesis. The screening efficiency of increased nuchal thickness and shortened long-bone length (standard biometry) and gross morphologic defects was determined for comparison. Multiple backward stepwise regression analysis was used to determine which subtle anomalies significantly correlated with Down syndrome detection rate and whether they increased Down syndrome detection over that with standard biometry and morphologic defects.

RESULTS: Although all subtle anomalies except two-vessel cord correlated with the presence of Down syndrome on univariate analysis, only echogenic bowel (Wald chi2 = 15.0211, p = 0.0001) and clinodactyly (Wald chi2 = 9.4273, p = 0.002) persisted in regression analysis of the subtle anomaly group. When either of the above-described anomalies was present, the detection rate for Down syndrome was 28.6%, p < 0.00001. For the combination of standard biometry (either increased nuchal thickness or short humerus) or gross anatomic defect, Down syndrome detection rate was 53.3% (p < 0.00000001). This increased to 63.2% (p < 0.00000001) when subtle anatomic defects (either echogenic bowel or clinodactyly) were included in the definition of an abnormal sonogram.

CONCLUSION: Subtle anomalies, of which echogenic bowel and clinodactyly are the most significant, further increase Down syndrome screening efficiency over standard biometry or the finding of gross anatomic defect. Our data appear to support the addition of subtle anomaly findings to ultrasonographic screening for Down syndrome.

Risk of Down syndrome and any clinically significant chromosome defect in pregnancies with abnormal triple-screen and normal targeted ultrasonographic results.

Bahado-Singh RO, Tan A, Deren O, Hunter D, Copel J, Mahoney MJ.

Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06520-8063, USA

Am J Obstet Gynecol 1996 Oct;175(4 Pt 1):824-9 Abstract quote

OBJECTIVE: Our purpose was to study prospectively the use of ultrasonographic biometry to refine the risk estimates for both Down syndrome and any clinically significant chromosome defect in women with abnormal biochemical triple-screen results.

STUDY DESIGN: Ultrasonographic biometry and anatomic survey were performed on study and control cases. Expected values for humerus, femur, combined humerus plus femur lengths, and abdominal circumference were generated on the basis of biparietal diameter obtained from a normal group. Threshold observed/expected values of each measurement for screening for Down syndrome and clinically significant chromosome defects were determined with receiver-operator characteristic curves. By stepwise logistic regression analysis the optimal screening parameters, including nuchal thickness, for detection of Down syndrome and clinically significant chromosome defect were determined. Risk tables for chromosome anomalies were developed on the basis of ultrasonography and triple-screen values.

RESULTS: Of 1034 cases at risk for Down syndrome (risk > or = 1/270) or trisomy 18 on the basis of triple-screen results, there were 11 cases of Down syndrome, 1 of trisomy 18, and 17 clinically significant chromosome defects. Abnormal nuchal thickness or observed/expected humerus length < 0.92 was the most sensitive parameter for Down syndrome detection. Abnormal nuchal thickness or observed/expected combined femur and humerus length < 0.90 was the most sensitive for significant chromosome defects. With abnormal biometry or anatomy the Down syndrome risk was 8 of 127 versus 1 of 753 in normals, odds ratio 50.4 (95% confidence interval 6.4 to 90.2), p < 0.00001, and the risk of significant defects was 11 of 90 versus 6 of 830 in normals, odds ratio 19.3 (95% confidence interval 6.4 to 60.5), p < 0.00001. In a pregnancy with a 1 in 270 triple-screen risk for Down syndrome, normal biometric and anatomic results reduce the risk to 1 in 2100.

CONCLUSION: Normal ultrasonographic anatomy and biometry significantly reduces the risk of both Down syndrome and any significant chromosome defects in pregnancies with abnormal triple-screen results.

Normal nuchal thickness in the midtrimester indicates reduced risk of Down syndrome in pregnancies with abnormal triple-screen results.

Bahado-Singh RO, Goldstein I, Uerpairojkit B, Copel JA, Mahoney MJ, Baumgarten A.

Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06520-8063, USA.

Am J Obstet Gynecol 1995 Oct;173(4):1106-10 Abstract quote

OBJECTIVE: Our purpose was to determine whether nuchal thickness measurement can identify the euploid fetuses in midtrimester pregnancies at increased risk for Down syndrome on the basis of maternal age and serum screening.

STUDY DESIGN: Nuchal thickness was obtained prospectively in 651 consecutive fetuses at 14 to 21 weeks' gestation and at > or = 1:270 risk for Down syndrome on the basis of unconjugated estriol, alpha-fetoprotein, and human chorionic gonadotropin levels. The risk of Down syndrome with a normal nuchal thickness was determined. A receiver-operator characteristic curve was used to determine a serum-based risk threshold below which the risk for Down syndrome was low. The prevalence of Down syndrome in fetuses with both a normal nuchal thickness and a below-serum-risk threshold was compared with prevalence in either those above threshold risk or with an abnormal nuchal thickness.

RESULTS: There were eight cases of trisomy 21 and one case each of 46,XX/47,XXX, 46,XY/47,XY, +7, and 46,XX, 11q-. The sensitivity of an abnormal nuchal thickness (> or = 6 mm) for detecting Down syndrome was four in eight (50%) (95%) confidence interval 15.3% to 84.6%). The risk of Down syndrome was significantly increased with an abnormal compared with a normal nuchal thickness, four in 13 (30.8%) versus four in 638 (0.6%), p < 0.0001. A risk threshold was defined at > or = 1:100 on the basis of the receiver-operator characteristic plot. Of 390 cases with a normal nuchal thickness and a serum risk estimate < 1:100, there were no cases of Down syndrome (0/390 vs 8/253, p = 0.002).

CONCLUSION: Normal nuchal thickness significantly reduces the risk of Down syndrome and may help reduce the number of amniocenteses done for abnormal triple screen results.

Prospective multicenter study of second-trimester nuchal skinfold thickness in unaffected and Down syndrome pregnancies.

Donnenfeld AE, Carlson DE, Palomaki GE, Librizzi RJ, Weiner S, Platt LD.

Department of Obstetrics and Gynecology, Pennsylvania Hospital, Philadelphia.


Obstet Gynecol 1994 Nov;84(5):844-7 Abstract quote

OBJECTIVE: To determine the distribution of nuchal skinfold thickness in normal and Down syndrome pregnancies and to evaluate the use of this sonographic measurement as a screening test for fetal Down syndrome.

METHODS: A prospective, multicenter, population-based study was performed by experienced obstetric sonographers on 1382 women with sonographically normal fetuses undergoing second-trimester amniocentesis for the indication of advanced maternal age. A standard, well-defined sonographic image was obtained at all collaborating centers. The distributions of nuchal skinfold thickness were compared between euploid and Down syndrome fetuses.

RESULTS: There were 1346 chromosomally normal pregnancies, 13 fetuses with Down syndrome (1:106), and 23 other chromosome abnormalities. Seventeen fetuses had measurements of 6 mm or greater, and one of these had Down syndrome. The median nuchal skinfold thickness in Down syndrome was 3.2 mm and in euploid fetuses was 3.1 mm. By the Mann-Whitney rank-sum test, there was no statistically significant difference in nuchal skinfold between the euploid and Down syndrome fetuses (P = .5). Overall, using a nuchal skinfold thickness of 6 mm or greater as a screening test, the detection rate for Down syndrome was one of 13 (8%), the false-positive rate was 16 of 1382 (1.2%), the positive predictive value was one of 17 (6%), and the probability of detecting Down syndrome was 6.5%.

CONCLUSION: In this investigation, excess nuchal skinfold thickness was a poor and unreliable screening test for Down syndrome.

CT scan and MRI  
Triple Test
Maternal serum AFP
Beta hCG


Alzheimer-like changes in brain>40 yrs
CARDIOVASCULAR Congenital heart defects (endocardial cushion defects consisting of ostium primum, atrial septal defect, atrioventricular valve malformations, and ventricular septal defects
FACIES Flat facies
Epicanthal folds
Abundant neck skin
GASTROINTESTINAL Intestinal stenosis
Umbilical hernia
Atresia of the esophagus
IMMUNE SYSTEM Predisposition to serious infections, usually T cell disturbances
Gap between first and second toe

Vesiculopustular eruptions in Down syndrome neonates with myeloproliferative disorders.

Nijhawan A, Baselga E, Gonzalez-Ensenat MA, Vicente A, Southern JF, Camitta BM, Esterly NB, Drolet BA.

Department of Dermatology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226, USA.

Arch Dermatol 2001 Jun;137(6):760-3 Abstract quote

BACKGROUND: Infants with Down syndrome are at increased risk for hematologic abnormalities, including leukemoid reaction, transient myeloproliferative disorder, and congenital leukemia. The differential diagnosis of a vesiculopustular eruption in an infant with Down syndrome and these hematologic abnormalities is broad and includes benign, self-limited disorders as well as life-threatening infections.

OBSERVATION: We describe 3 newborns with Down syndrome and vesiculopustular eruptions associated with myeloproliferative disorders during the neonatal period. These lesions differ from other neonatal vesicular eruptions in that they have a unique distribution, display pathergy, and contain immature hematopoietic cells similar to circulating blast cells. Resolution occurs without treatment as the hematologic disorder subsides.

CONCLUSIONS: Infants with Down syndrome and hematologic abnormalities may have a cutaneous eruption that has characteristic clinical and histopathologic findings. It is possible that this eruption has been unrecognized in the past because of its self-limited course. Whether this eruption is a prognostic factor for the subsequent development of leukemia is uncertain.


Acute leukaemia in children with Down syndrome: a population-based Nordic study.

Zeller B, Gustafsson G, Forestier E, Abrahamsson J, Clausen N, Heldrup J, Hovi L, Jonmundsson G, Lie SO, Glomstein A, Hasle H; Nordic Society of Paediatric Haematology and Oncology (NOPHO).

Department of Paediatrics, National Hospital of Norway, N-0027 Oslo, Norway.
Br J Haematol. 2005 Mar;128(6):797-804. Abstract quote  

To determine the epidemiology and outcome of children with Down syndrome (DS) diagnosed with acute leukaemia in the Nordic countries, data registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) population-based leukaemia registry were analysed.

Of 3494 children with acute leukaemia diagnosed between July 1984 and December 2001, 136 patients (3.9%) with DS were identified. 2.1% of the children with acute lymphoid leukaemia (ALL) and 14.0% of the children with acute myeloid leukaemia (AML) had DS. In ALL, DS patients had similar age and sex distribution and no major differences in blood counts compared with non-DS children. None of the DS patients had T cell leukaemia. Outcome was inferior to that of non-DS children and treatment results did not improve over time.

In AML, DS patients showed a significant female predominance and all but one were <5 years old. DS patients with AML had significantly lower platelet and white blood cell counts and two-thirds were type M7 as according to the French-American-British classification. None of the patients <5 years of age had typical AML cytogenetic aberrations. Outcome was far better in the DS group.

DS patients treated for AML after 1992 had an excellent outcome (probability of event-free survival, 83 +/- 6%). The high proportion of female DS patients with AML is unexplained. The differing treatment results in AML versus ALL need further evaluation and represent a challenge for the coming years.

Leukemia in Down syndrome: a review.

Zipursky A, Poon A, Doyle J.

Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada

Pediatr Hematol Oncol 1992 Apr-Jun;9(2):139-49 Abstract quote

The incidence of leukemia is higher in children with Down syndrome (DS) than in normals. In approximately 50% of cases the type of leukemia is acute megakaryoblastic leukemia (AMKL) and it occurs during the first 4 years of life.

The leukemic cell also has features of erythroid progenitors and therefore appears to be a precursor cell with biphenotypic properties. In addition, newborns with DS frequently develop transient leukemia (TL), which is characterized by the presence of megakaryoblasts in the blood which disappear during the first 1-3 months of life.

The incidence of this disorder is unknown although preliminary studies suggest that megakaryoblasts may be found frequently in the blood of DS newborns. TL does not occur in normal newborn infants. Although TL disappears spontaneously, many of these children will develop AMKL at 1-4 years of age.

Recent surveys suggest that 20-30% of newborns with TL will develop AMKL. Preliminary evidence suggests that TL is a clonal proliferation, can be fatal, and may occur in a specific subgroup of DS children.

The observations in this report are drawn from our own experience, reports in the literature, and data accumulated in the Canadian Down Syndrome Leukemia Registry.

Transient leukemia (transient myeloproliferative disorder, transient abnormal myelopoiesis) of down syndrome.

Departments of Pathology and Pediatrics, Saint Louis University School of Medicine, Saint Louis, MO.


Adv Anat Pathol. 2006 Sep;13(5):256-62. Abstract quote

Transient leukemia of Down syndrome (DS-TL), also known as transient myeloproliferative disorder of Down syndrome (DS) and transient abnormal myelopoiesis of DS, occurs in approximately 10% of DS neonates and in phenotypically normal neonates with trisomy 21 mosaicism. In DS-TL, peripheral blood analysis shows variable numbers of blasts and, usually, thrombocytopenia; other cytopenias are uncommon.

Bone marrow characteristics of DS-TL are, likewise, variable, though (in contrast to other leukemias) the bone marrow blast differential can be lower than the peripheral blood blast differential.

The blasts of DS-TL typically show light microscopic, ultrastructural, and flow cytometric evidence of megakaryocyte differentiation. DS-TL neonates have a approximately 15% risk of developing potentially fatal liver disease and show <10% incidence of hydrops fetalis. Additional manifestations of DS-TL include cutaneous involvement, hyperviscosity, myelofibrosis, cardiopulmonary failure, splenomegaly, and spleen necrosis. Despite its typical transient nature, 20% to 30% of DS-TL patients develop overt (nontransient) acute leukemia, usually within 3 years and typically of the M7 phenotype (acute megakaryoblastic leukemia).

The pathogenesis of DS-TL (and of subsequent acute leukemia) involves mutation of GATA1 (on chromosome X), which normally encodes a transcription factor integral to normal development of erythroid, megakaryocytic, and basophilic/mast cell lines. The pathogenetic role of trisomy 21 in DS-TL is unclear.

Though indications for chemotherapy in DS-TL have not been firmly established, the blasts of DS-TL are sensitive to low-dose cytosine arabinoside.

Telomerase and the benign and malignant megakaryoblastic leukemias of Down syndrome.

Holt SE, Brown EJ, Zipursky A.

Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.

J Pediatr Hematol Oncol 2002 Jan;24(1):14-7 Abstract quote

The most common form of leukemia in Down syndrome patients is megakaryoblastic leukemia. There are two forms of the disease. Transient leukemia (TL) is a form of megakaryoblastic leukemia that occurs in newborns with Down syndrome and usually disappears spontaneously within the first 3 months of life. Acute megakaryoblastic leukemia (AMKL) occurs in Down syndrome children within the first 4 years of life and is fatal without treatment. The megakaryoblasts of TL and AMKL are indistinguishable by light and electron microscopy; yet, TL is benign and AMKL is malignant. One of the hallmarks of many malignancies is the expression of telomerase. It is therefore hypothesized that the transient, benign form of megakaryoblastic leukemia (TL) would not contain telomerase activity, whereas telomerase would be demonstrable in the malignant form of the disease.

Telomerase activity was determined in the blood and/or bone marrow aspirates in 29 cases of AMKL and 34 cases of TL. The authors found telomerase activity in 15 of 29 (52%) cases, of AMKL and in only 4 of 34 (12%) cases of TL (P < 0.001). Furthermore, three of the four telomerase-positive TL cases were particularly severe, of which two were fatal.

Telomerase activity is found frequently in the leukemic cells of the malignant form of megakaryoblastic leukemia but rarely in the benign form of the disease (TL). Observations provide evidence that telomerase may be a critical factor for the malignant conversion of leukemic cells.

Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric Oncology Group Study.

Al-Kasim F, Doyle JJ, Massey GV, Weinstein HJ, Zipursky A; Pediatric Oncology Group.

Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.


J Pediatr Hematol Oncol 2002 Jan;24(1):9-13 Abstract quote

Transient leukemia (TL or transient myeloproliferative disorder) occurs in approximately 10% of newborn infants with Down syndrome.

The disorder is characterized by the presence of megakaryoblasts in the peripheral blood; most cases resolve spontaneously within the first 3 months of life, and the child is well thereafter. However, there are cases in which a severe, potentially lethal form of disease develops, manifesting as hepatic fibrosis or cardiopulmonary failure. Hitherto, the incidence of these severe forms of the disease has not been reported.

A prospective study of TL was conducted by the Pediatric Oncology Group (POG Study 9481) in which 48 children with TL were identified. Life-threatening disease occurred in nine patients (19%); seven had hepatic fibrosis and two had cardiopulmonary failure. Five children died of the disease within the first 3 months of life, none of whom received antileukemic therapy. One patient died on day 31 after receiving minimal therapy within 1 day of death.

Three children received low-dose cytosine arabinoside (Ara-C) (0.4-1.5 mg/kg every 12 hours for 5 or 7 days). In all these patients, the disease resolved. It is concluded that potentially lethal disease is relatively common in TL, and the available evidence suggests that these diseases are responsive to low-dose Ara-C therapy.

Acute megakaryoblastic leukemia after transient myeloproliferative disorder with clonal karyotype evolution in a phenotypically normal neonate.

Polski JM, Galambos C, Gale GB, Dunphy CH, Evans HL, Batanian JR.

Department of Pathology, University of South Alabama College of Medicine, Mobile, USA.


J Pediatr Hematol Oncol 2002 Jan;24(1):50-4 Abstract quote

We report a case of transient myeloproliferative disorder (TMD) in a neonate without features of Down syndrome (DS) with clonal karyotype evolution, after apparent spontaneous resolution of TMD, but eventually progressing to acute megakaryoblastic leukemia (AMKL).

The patient had petechiae, thrombocytopenia, and blastemia. Trisomy 21 with a satellited Y chromosome (Yqs) was found in proliferating blasts. A stimulated peripheral blood culture confirmed the constitutional origin of the Yqs, but did not reveal the presence of any trisomic 21 cell. By the age of 3 months, clonal chromosome evolution in the form of an interstitial deletion of the long-arm of chromosome 13 [del(13)(q13q31)] was detected along with trisomy 21 in unstimulated bone marrow cultures. However, remission was achieved without treatment at the age of 4 months. Trisomy 21 and del(13)(q13q31) were not identified in either cytogenetics or fluorescence in situ hybridization studies at that time.

The child was asymptomatic until the age of 20 months when anemia and thrombocytopenia prompted a bone marrow biopsy, revealing changes consistent with AMKL. The remission proceeded by clonal karyotype evolution in a neonate with TMD demonstrates that clonal karyotype evolution does not indicate an immediately progressive disease. However, the development of AMKL after TMD in this case illustrates the increased risk for leukemia in TMD cases, even without DS.

The gradual clonal evolution of the blasts in our patient suggests that "multiple hits" oncogenesis applies to TMD progression to acute leukemia.

Transient Myeloproliferative Disorder and Acute Myeloid Leukemia in Down Syndrome An Immunophenotypic Analysis

Nitin J. Karandikar, MD, PhD, Deborah B. Aquino, MD, Robert W. McKenna, MD, and Steven H. Kroft, MD

Am J Clin Pathol 2001;116:204-210 Abstract quote

Immunophenotypic analysis of transient myeloproliferative disorder (TMD) and acute myeloid leukemia (AML) using multiparameter flow cytometry might provide insight into their relationship.

We retrospectively analyzed the expression of multiple lymphoid, myelomonocytic, and megakaryocytic antigens on blast proliferations in 18 patients with Down syndrome (DS; AML, 9; TMD, 9). The AMLs and TMDs shared several immunophenotypic characteristics. Blasts in all expressed CD45, CD38, and CD33; most AMLs and all TMDs were CD36+; and the majority expressed CD41 and CD61, suggesting megakaryocytic differentiation. The majority of cases were CD34+, CD14–, and CD64–. There was aberrant expression of the T-cell–associated antigen CD7 in most AMLs and TMDs. CD56 was expressed aberrantly in 5 AMLs and 7 TMDs.

The major difference between the disorders was the pattern of expression of myeloid markers CD11b and CD13; each was expressed in 8 AMLs but only 2 TMDs. Blasts were HLA-DR–positive in 3 AMLs vs 7 TMDs. Blasts in TMD and AML in DS have a characteristic immunophenotype distinct from AML in other settings. The immunophenotypic similarities suggest a biologic relationship between the disorders; however, distinct immunophenotypic differences also were observed.

Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome.

Zipursky A, Brown EJ, Christensen H, Doyle J.

Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

Clin Lab Med 1999 Mar;19(1):157-67 Abstract quote

Transient Myeloproliferative Disorder (Transient Leukemia) is found in approximately 10% of newborn infants with Down Syndrome.

It is characterized by the large numbers of megakaryoblasts in the peripheral blood, variable thrombocytopenia and, in a minority of cases, by a lethal course with hydrops fetalis or progressive hepatic fibrosis. Evidence is presented that this disease is truly leukemia, which, in most cases, recovers spontaneously.

There is evidence that hematopoiesis is abnormal in Down Syndrome children who do not have leukemia. These abnormalities of red cells, platelets, and granulocytes are reviewed.

Leukemia and/or myeloproliferative syndrome in neonates with Down syndrome.

Zipursky A, Brown E, Christensen H, Sutherland R, Doyle J.

Department of Pediatrics, Hospital for Sick Children, University of Toronto, Ontario, Canada.

Semin Perinatol 1997 Feb;21(1):97-101 Abstract quote

Approximately 10% of newborn infants with Down Syndrome develop a form of megakaryoblastic leukemia which usually disappears spontaneously during the first months of life.

The evidence that this "Transient Leukemia" is truly leukemia includes the following: it is clonal proliferation, it can be fatal and tissue infiltration of leukemic cells occurs. Also in approximately 25% of cases that recover, Acute Megakaryoblastic Leukemia will develop in the first four years of life, which, if not treated, is fatal. Evidence regarding the megakaryoblastic nature of the leukemic cells is presented as well as a description of the lethal forms of the disease.

The study of Transient Leukemia is of considerable importance because it can provide insight into both the nature of leukemia and its relation to trisomy 21.


Transient abnormal myelopoiesis of infancy associated with trisomy 21.

Homans AC, Verissimo AM, Vlacha V.

Department of Pediatrics, University of Vermont College of Medicine, Burlington 05405.


Am J Pediatr Hematol Oncol 1993 Nov;15(4):392-9 Abstract quote

PURPOSE: A unique myelodysplastic syndrome referred to as transient abnormal myelopoiesis (TAM) has been reported to occur primarily in infants with Down's syndrome (DS) or other abnormalities of chromosome 21. This disorder raises basic questions regarding the pathogenesis of leukemia, yet its natural history is poorly documented and derives from small series and isolated case reports.

PATIENTS AND METHODS: To better characterize TAM, we accumulated data on 35 cases identified through a questionnaire mailed to pediatric oncologists in the United States. These cases, pooled with two that we recently encountered, and 58 comparable cases reported in the literature comprise a series of 95 cases of TAM in DS.

RESULTS: The patients in this series were notable for the high morbidity and mortality of this reportedly benign condition. Eleven percent of the patients died during the initial event, and the overall mortality for the entire series was 27%. Twenty-eight of the 85 patients (33%) who survived the initial event developed a subsequent hematologic disorder, most often acute nonlymphocytic leukemia, at a median age of 16 months.

CONCLUSIONS: No initial clinical or hematologic features predicted the development of a subsequent hematologic disorder. However, those patients initially mosaic for the presence of trisomy 21 did not develop subsequent abnormalities. This series reviews questions regarding leukemogenesis in DS and underscores the importance of conducting future prospective studies of this unique hematologic disorder.



Functional status of school-aged children with Down syndrome.

Leonard S, Msall M, Bower C, Tremont M, Leonard H.

TVW Telethon Institute for Child Health Research, Perth, Western Australia, Australia.

J Paediatr Child Health 2002 Apr;38(2):160-5 Abstract quote

OBJECTIVE: To field test, in questionnaire format, the Functional Independence Measure for Children (WeeFIM, a schedule usually administered by interview) on parents of a cohort of school-aged children with Down syndrome.

METHODS: The parents of 211 Western Australian children with Down syndrome participated in the present study, representing 79.9% of all children with Down syndrome in the State. Subjects were identified using two sources: (i) the Birth Defects Registry; and (ii) the Disability Services Commission.

RESULTS: The total WeeFIM score was 106.2 +/- 17.0 (mean +/- SD) out of a possible 126. Girls scored higher than boys (108.6 vs 103.6; P = 0.05). Scores increased across all age groups (P < 0.0001), even relative to normative data. Performance was strongest in the transfer and locomotion domains and weakest in social cognition.

CONCLUSION: We found that severe functional limitations are rare in school-aged children with Down syndrome. Some support and supervision are required for complex self-care, communication and social skill tasks. This study demonstrates the feasibility of using the WeeFIM for collecting population survey data in children with developmental disability. This may be useful for the longitudinal tracking of such populations, as well as the monitoring of response to interventions.


Growth curves of children with Down syndrome.

Toledo C, Alembik Y, Aguirre Jaime A, Stoll C.

Service de Genetique Medicale, Centre Hospitalo-Universitaire, Strasbourg, France.

Ann Genet 1999;42(2):81-90 Related Articles, Links

Growth curves of children with Down syndrome.

Toledo C, Alembik Y, Aguirre Jaime A, Stoll C.

Service de Genetique Medicale, Centre Hospitalo-Universitaire, Strasbourg, France.

Growth curves of 105 children with Down syndrome (50 boys and 55 girls) were established. At birth height, weight and head circumference of Down syndrome children were lower than these parameters in controls. This delay remained stable until puberty. For weight there was no clear-cut pubertal growth spurt. For stature, the prepubertal growth spurt occurred earlier (at the age of 11 years in boys and 9 1/2 years in girls) than in controls but was less marked. As a result, Down syndrome patients had a short stature with a quite normal weight.

These reference curves, available since prenatal diagnosis of Down syndrome is performed routinely, are helpful for monitoring normal and abnormal development in Down syndrome patients.

Growth charts for children with Down syndrome: 1 month to 18 years of age.

Cronk C, Crocker AC, Pueschel SM, Shea AM, Zackai E, Pickens G, Reed RB.

Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia.

Pediatrics 1988 Jan;81(1):102-10 Abstract quote

Centile charts for assessment of stature and weight reflecting expected deficient size and growth rate of home-reared children with Down syndrome are presented for two age intervals, 1 to 36 months and 2 to 18 years, based on 4650 observations on 730 children.

Data were pooled and used to estimate five centiles which were smoothed using a flexible mathematical function. These data corroborate other studies of growth in children with Down syndrome demonstrating deficient growth rate throughout the growing period, but most marked in infancy and again at adolescence. Children with Down syndrome in the present sample were taller than those from institutionalized samples at all ages throughout the growing period. Children with moderate or severe congenital heart disease on average were 1.5 to 2.0 cm shorter and about 1 kg lighter than those without or with only mild disease.

Mean weight and weight divided by stature squared show that children with Down syndrome have a tendency to be overweight beginning in late infancy and throughout the remainder of the growing years.


Mortality of people with mental retardation in California with and without Down syndrome, 1986-1991.

Strauss D, Eyman RK.

Department of Statistics, University of California, Riverside 92521, USA.

Am J Ment Retard 1996 May;100(6):643-53 Abstract quote

Mortality of people with mental retardation receiving services in California was examined. The large population (N = 118,653) enabled us to work directly with mortality rates at specific ages. Up to about age 35, mortality rates of people with Down syndrome were comparable to those of people with mental retardation due to other causes. Subsequently, the increase was much more rapid in the group with Down syndrome.

Mortality rates of individuals with Down syndrome doubled every 6.4 years compared to 9.6 years for people without Down syndrome.

Life tables were constructed; the remaining life expectancy of a 1-year-old child with Down syndrome with mild/moderate retardation was 55 years and with profound mental retardation, 43 years.

Life expectancy of persons with Down syndrome.

Eyman RK, Call TL.

University of California, Riverside Research Group, Lanterman Developmental Center, Pomona 91769.

Am J Ment Retard 1991 May;95(6):603-12 Abstract quote

The longevity of people with Down syndrome being served by the California Department of Developmental Services was examined in terms of a number of variables known to be related to early mortality.

The findings indicated that the predictors of survival for people with Down syndrome were not different from the variables related to mortality among people with mental retardation in general. A lack of mobility or feeding skills were better predictors of an early death than were medical problems associated with congenital heart disease.

Life expectancy estimates of clients with Down syndrome who lacked mobility or eating skills were found to be poor as compared to individuals who had Down syndrome but did not have these problems regardless of the presence of heart disease.


Cancer incidence in persons with Down syndrome in Israel.

Boker LK, Merrick J.

Julius Center for General Practice and Patient Oriented Research, University Medical Center Utrecht, The Netherlands.

Downs Syndr Res Pract 2002 Mar;8(1):31-6 Abstract quote

The purpose of this study was to assess the incidence rates of leukaemia and other malignancies in persons with Down syndrome in Israel. The target population consisted of all persons with Down syndrome in the period of 1948-1995 and the study population was divided into two subgroups: (1) Persons born in Israel between 1979-95 (registry group) and (2) Persons currently or past-institutionalised, born before 1979 (institution group).

The study population was linked to the Cancer Registry and cases that had been diagnosed through December 1995 were subsequently identified. The observed incidence rates were compared to expected rates in the general population. Standardised Incidence Ratios (SIR) and 95% confidence intervals were computed for each disease category.

Analyses of results were performed separately for each subgroup of our study population. In the registry group seven cancer cases were observed as compared to 1.5 expected (SIR = 4.67 95% CI 1.9-9.6), all of which were leukaemia cases. For the institution group a total of 17 cancer cases were observed compared to 12.8 expected. These included four cases of leukaemia (SIR = 6.90 95% CI 1.9-17.7). An excess of gastric cancer in males, based on two cases (SIR = 11.9 95% CI 1.3-42.9) was also observed.

The significant excess of leukaemia in the Down syndrome population in Israel is in accordance with other international studies. The excess of gastric cancer in males with Down syndrome, which has not been reported before, should be further explored.


Clinical aspects of Down syndrome from infancy to adulthood.

Pueschel SM.

Department of Pediatrics, Rhode Island Hospital, Providence 02915.

Am J Med Genet Suppl 1990;7:52-6 Abstract quote

In past decades, most individuals with Down syndrome were usually not afforded adequate medical care. Many children with Down syndrome were institutionalized and they were often deprived of all but the most elementary medical services. Fortunately, there have been major improvements in the health care provision during the past 20 years. Professionals who are providing services to persons with Down syndrome need to be aware of those clinical conditions that are more often observed in this population.

Certain congenital anomalies (congenital cataracts, anomalies of the gastrointestinal tract, and congenital heart disease) often require immediate attention, as some of them may be life threatening. During the subsequent childhood years a number of clinical conditions and disorders such as infectious diseases, increased nutritional intake, periodontitis, seizure disorders, sleep apnea, visual impairment, audiologic deficits, thyroid dysfunction, and skeletal problems usually occur at a higher prevalence. During adolescence specific aspects of maturation and certain health issues (skin infections, thyroid disorders, increased weight gain, and others) as well as mental health concerns need to be taken into consideration. Similar concerns may also be observed during adulthood which in addition is often marked by accelerated aging and the threat of Alzheimer disease in some persons with Down syndrome. Special attention needs to be paid to these disorders and conditions during the lifetime of a person with Down syndrome.

Appropriate medical care should be provided to and no form of treatment should be withheld from a person with Down syndrome that would be given unhesitatingly to an individual without this chromosome disorder.


Health care management of adults with Down syndrome.

Smith DS.

Department of Family and Community Medicine, Medical College of Wisconsin, Milwaukee 53226, USA.

Am Fam Physician 2001 Sep 15;64(6):1031-8 Abstract quote

The family physician's holistic approach to patients forms the basis of good health care for adults with Down syndrome. Patients with Down syndrome are likely to have a variety of illnesses, including thyroid disease, diabetes, depression, obsessive-compulsive disorder, hearing loss, atlantoaxial subluxation and Alzheimer's disease. In addition to routine health screening, patients with Down syndrome should be screened for sleep apnea, hypothyroidism, signs and symptoms of spinal cord compression and dementia.

Patients with Down syndrome may have an unusual presentation of an ordinary illness or condition, and behavior changes or a loss of function may be the only indication of medical illnesses. Plans for long-term living arrangements, estate planning and custody arrangements should be discussed with the parents or guardians.

Because of improvements in health care and better education, and because more people with this condition are being raised at home, most adults with Down syndrome can expect to function well enough to live in a group home and hold a meaningful job.


Primary care of infants and young children with Down syndrome.

Saenz RB.

Department of Family Medicine, University of Mississippi Medical Center, Jackson 39216, USA.

Am Fam Physician 1999 Jan 15;59(2):381-90, 392, 395-6 Abstract quote

Down syndrome is caused by triplicate material of chromosome 21. The syndrome has a variable physical expression, but congenital cardiac defects, transient myelodysplasia of the newborn and duodenal atresia are highly specific for this chromosomal disorder.

Routine health maintenance is important because infants and children with Down syndrome are more likely to have otitis media, thyroid disease, congenital cataracts, leukemoid reactions, dental problems and feeding difficulties. Since infants with this syndrome are prone to respiratory infections, immunization recommendations should be followed closely. Motor, language, social and adaptive skills should be assessed at each office visit. The psychosocial aspects of care should be discussed with the parents of an infant with Down syndrome. If necessary, the parents should be referred to family support and specialty resources. Institutionalization of infants with Down syndrome is now unlikely.

With newer surgical techniques, early therapy to minimize developmental delay and proper health supervision, the functional prognosis for infants with Down syndrome is considerably improved.

Dramatic improvement in Down syndrome-associated cognitive impairment with donepezil.

Kondoh T, Amamoto N, Doi T, Hamada H, Ogawa Y, Nakashima M, Sasaki H, Aikawa K, Tanaka T, Aoki M, Harada J, Moriuchi H.

Department of Pediatrics, Nagasaki University Hospital, Sakamoto 1-7-1, Nagasaki 852-8501, Japan.
Ann Pharmacother. 2005 Mar;39(3):563-6. Epub 2005 Feb 8. Abstract quote  

OBJECTIVE: To report 2 cases of patients with Down syndrome and severe cognitive impairment who gained dramatic improvements in quality of life (QOL) upon donepezil treatment.

CASE SUMMARIES: Case 1. A 38-year-old woman with Down syndrome, diagnosed with secondary progressive dementia when her mental state had deteriorated rapidly after graduation from junior high school, started donepezil treatment. The loading dose was 3 mg/day and was increased to 5 mg/day for maintenance. One month after the dose was increased, adverse effects such as soft stool and urinary incontinence appeared. These adverse effects disappeared when the dose was decreased again to 3 mg/day. Her QOL improved dramatically with this minimal dose. She recovered verbal and written communication skills that she had lost for the past 21 years. Case 2. A 22-year-old man with Down syndrome, who had been diagnosed as having severe mental retardation, was put on donepezil therapy. Both loading and maintenance doses were 3 mg/day. His QOL had also dramatically improved, with some recovery in verbal communication. Transient agitation/violence and transient muscle weakness appeared during the first few months of treatment.

DISCUSSION: Patients with Down syndrome may be more sensitive to donepezil therapy than others and may benefit from this medicine, although they may also have adverse effects more frequently.

CONCLUSIONS: Donepezil may be a useful medicine for some patients with Down syndrome with severe cognitive impairment or mental retardation if the adverse effects are manageable.
A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease--pilot study.

Prasher VP, Huxley A, Haque MS; Down syndrome Ageing Study Group.

Monyhull Hospital, Monyhull Hall Road, Kings Norton, Birmingham, B30 3QB, UK.
Int J Geriatr Psychiatry. 2002 Mar;17(3):270-8. Abstract quote  

BACKGROUND: Donepezil Hydrochloride (Aricept) is a selective anticholinesterase inhibitor developed for the treatment of Alzheimer's disease (AD). This study investigated the safety and efficacy of the drug to treat Down syndrome (DS) adults with mild to moderate AD.

METHOD: This was a 24-week, double blind, placebo controlled, parallel-group trial. Patients were randomized to receive placebo or donepezil (5 mg per day during the first four weeks, and then 10 mg per day thereafter). Primary efficacy was measured using the Dementia Scale for Mentally Retarded Persons (DMR), and secondary efficacy was measured using the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI) and by the Adaptive Behavior Scale (ABS).

RESULTS: A total of 30 DS patients with AD entered the study of which 27 were included in the subsequent data analysis. The donepezil group had non-statistically significant reduction in deterioration in DMR, SIB, and ABS mean scores relative to the placebo group. However NPI scores showed less improvement in the donepezil group when compared to the placebo group. Fifty percent of subjects in the donepezil group showed improvement in mean DMR scores at the end point compared to baseline, when compared to 31% on placebo. There were no life threatening adverse effects associated with treating adults with DS with donepezil. A number of side-effects did occur including diarrhoea, insomnia, fatigue, and nausea.

CONCLUSION: Donepezil Hydrochloride administered once a day appears to be generally well tolerated and safe in DS adults who have AD. There is some possible efficacy in the treatment of symptoms of mild to moderate Alzheimer's disease in this population, although the sample size of this study was too small for statistical significance. It is recommended that donepezil, with the appropriate precautions, should be considered for the treatment of AD in adults with DS as deemed by a specialist.

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