The incidence of this form is strongly influenced by maternal age (1 in 1550 births in women younger than 20 years, increasing to 1 in 25 in women older than 45 years). In 95% of these cases, the extra chromosome is maternal in origin.

- A translocation variant, making up 4% of all cases, has extra chromosomal material derived from inheritance of a parental chromosome bearing a translocation of the long arm of chromosome 21 to chromosome 22 or 14 (Eg., 46,XX,der(14, 21) (q10,q10), +21.

Because the fertilized ovum already possesses two normal autosomes 21, the translocated chromosomal fragment provides the same triple-gene damage as trisomy 21.

Such cases are frequently (but not always) familial because the parent is a carrier of a robertsonian translocation. Such a rearrangement may also occur during gametogenesis.

- Mosaic variants make up about 1% of all cases, they have a mixture of cells with normal chromosome number and cells with extra chromosome 21.

Clinical feature:

- Flat facies with oblique palpebral fissures and epicanthic folds.

- Nasal bone and nuchal fold are efficient markers for Down syndrome. Absent nasal bone was a better predictor of Down syndrome, compared with nuchal fold, and should be a standard marker when a second-trimester genetic sonogram is performed.

- Severe mental retardation

- Congenital heart disease, especially septal defects, responsible for the majority of deaths in infancy and childhood.

- 10 to 20-fold increased risk of developing acute leukemia. It appears that the extra genetic material in chromosome 21 confers a proliferative advantage to hematopoietic stem cells, and may make them more prone to further karyotypic changes leading to leukemia. Megakaryocytic proliferative disorders are more common in patients with Down's syndrome. The spectrum of myeloproliferative disorders including myelofibrosis, myeloid metaplasia, and megakaryoblastic leukemia is seen in these patients.

- Sub-clinical hypothyroidism was the most common thyroid abnormality in children with Down's syndrome. A timely-scheduled evaluation of thyroid function is needed to establish the natural course of this abnormality and the proper management guideline.

Down's syndrome and leukemia: mechanism of additional chromosomal abnormalities. Am J Ment Defic. 1978;82(6):542-8.

There is an increased incidence of acute leukemia in patients with Down's syndrome patients have a trisomy-21 chromosomal pattern, and chromosomal abnormalities can be seen in acute leukemia. It is possible that the increased incidence of acute leukemia in Down's syndrome persons may be due in part to their chromosomal abnormalities. Such abnormalities, some appearing in a stepwise clonal evolution, were found in five Down's syndrome patients, four with acute leukemia and one with abnormal regulation of leukopoiesis. Morphological abnormal chromosomes were also found in three patients. These chromosomal abnormalities are similar to those seen in non-Down's syndrome leukemic patients. There is suggestive evidence for clonal evolution hypothesis of luekemogenesis in non-Down's syndrome patients. The abnormal chromosomal pattern reported in our Down's syndrome patients could be the result of nondisjunction in mitosis, and leukemia may be the phenotypical expression of this nondisjunction.

Trisomy 21 in neoplastic cells.Am J Med Genet Suppl.1990;7:262-6.

Trisomy 21 as an acquired clonal chromosome change has been described in 642 of the 10,625 human neoplasms with chromosome aberrations known from the cytogenetic literature. A total of 590 of the 642 cases (92%) are hematologic disorders and malignant lymphomas. The incidence of trisomy 21 is similar (4.1%-6.7%) in acute myeloid leukemia (AML), chronic myeloid leukemia, myeloproliferative disorders, myelodysplastic syndromes, chronic lymphoproliferative disorders, and malignant lymphomas; it is substantially higher (14.8%) in acute lymphocytic leukemia (ALL). In most cases, the extra chromosome 21 is present together with other numerical and/or structural changes. Acquired trisomy 21 is the only karyotypic abnormality in only 0.4%. Trisomy 21 has never been reported as the sole anomaly in a solid tumor. The cytogenetic literature contains information on 62 patients with constitutional trisomy 21 and a malignant disorder in which the tumor cells have been analyzed by banding techniques. Thirty-four of the 62 patients had AML, 16 had ALL, and 2 had acute undifferentiated leukemia. The 52 leukemic Down syndrome (DS) cases account for 1.4% of the total acute leukemias, an overrepresentation that parallels the generally increased risk of leukemia development in DS. Sixty-three percent of the ALL patients and 79% of those with AML had additional changes superimposed on constitutional trisomy 21. These included several of the characteristic primary leukemia-associated aberrations: 5q-, 7q-, +8, and t(8;21) in AML, and t(1;19), t(4;11), 6q-, and 14q + in ALL. Thus, it seems that the pattern of acquired karyotypic changes is similar in patients with DS and in individuals with a normal constitutional karyotype.

- Premature Alzheimer disease in those who survive after 35 years of age.

Alzheimer's disease in Down syndrome: neurobiology and risk. Ment Retard Dev Disabil Res Rev. 2007;13(3):237-46.

Down syndrome (DS) is characterized by increased mortality rates, both during early and later stages of life, and age-specific mortality risk remains higher in adults with DS compared with the overall population of people with mental retardation and with typically developing populations. Causes of increased mortality rates early in life are primarily due to the increased incidence of congenital heart disease and leukemia, while causes of higher mortality rates later in life may be due to a number of factors, two of which are an increased risk for Alzheimer's disease (AD) and an apparent tendency toward premature aging. In this article, we describe the increase in lifespan for people with DS that has occurred over the past 100 years, as well as advances in the understanding of the occurrence of AD in adults with DS. Aspects of the neurobiology of AD, including the role of amyloid, oxidative stress, Cu/ZN dismutase (SOD-1), as well as advances in neuroimaging are presented. The function of risk factors in the observed heterogeneity in the expression of AD dementia in adults with DS, as well as the need for sensitive and specific biomarkers of the clinical and pathological progressing of AD in adults with DS is considered.

- Serious infections resulting from abnormal immune responses.

Down syndrome: a novel risk factor for respiratory syncytial virus bronchiolitis--a prospective birth-cohort study.Pediatrics. 2007 Oct;120(4):e1076-81.

OBJECTIVES: Respiratory syncytial virus is the single-most important cause of lower respiratory tract infections in children. Preterm birth and congenital heart disease are known risk factors for severe respiratory syncytial virus infections. Although Down syndrome is associated with a high risk of respiratory tract infections, little is known about the incidence of respiratory syncytial virus infections in this group. The aim of our study was to determine the incidence of respiratory syncytial virus lower respiratory tract infection-associated hospitalization among children with Down syndrome. PATIENTS AND METHODS: We performed a retrospective observational study and a prospective nationwide birth-cohort study of children with Down syndrome. The retrospective cohort comprised 176 children with Down syndrome. A birth cohort of 219 children with Down syndrome was prospectively followed until 2 years of age. All 276 siblings of the birth cohort were used as controls. RESULTS: Of the 395 patients with Down syndrome, 180 (45.6%) had a known risk factor for severe respiratory syncytial virus infections; 39 (9.9%) of these were hospitalized for respiratory syncytial virus lower respiratory tract infections. Two control children (0.7%) versus 9 term children with Down syndrome without congenital heart disease (7.6%) were hospitalized for respiratory syncytial virus lower respiratory tract infections. The median duration of hospitalization was 10 days; mechanical ventilation was required for 5 children (12.8%). CONCLUSIONS: This is the first study, to our knowledge, to demonstrate that Down syndrome is a novel independent risk factor for severe respiratory syncytial virus lower respiratory tract infections. These findings should prompt studies to investigate possible mechanisms that underlie severe respiratory syncytial virus lower respiratory tract infections in children with Down syndrome. The effect of respiratory syncytial virus prophylaxis in this specific population needs to be established.

The arthropathy of Down syndrome is an underrecognized condition that results in chronic disability and functional impairment in a population already at significant risk. Children with Down syndrome are predisposed to autoimmune disorders, but arthritis is overlooked in surveillance guidelines. To maximize joint function and quality of life, providers caring for children with Down syndrome need a high index of suspicion for the related arthropathy.

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