Aetiology
In the mid-1800s, several physicians described a group of patients with similar characteristics consisting of intellectual disability and specific facial features, including a flat face, round cheeks, epicanthal folds, and a protruding tongue.[6][7] Dr J. Langdon Down emphasised that affected individuals with Down's syndrome (DS) can be distinguished from the heterogeneous group of those with intellectual disabilities based on their distinct physical features, and the condition was named Down's syndrome after him.
It was not until 1959 that cytogenetic techniques became available, and thus DS was determined to be caused by an extra chromosome 21, or trisomy 21.[8] Further, with the introduction of chromosome staining and karyotyping, it became possible to identify the underlying types of chromosomal findings in DS: standard trisomy 21, chromosome translocations, and mosaicism.
In the mid-1960s, Penrose suggested that the most important risk factor is advanced maternal age as a cause of meiotic non-disjunction.[9] Later, population-based studies also indicated that over 90% of non-disjunction errors resulting in trisomy 21 occur in the oocyte, most during meiosis I.[5][10][11] However, the total number of pregnancies is far greater among women aged <35 years than among women >35 years and, hence, most newborns with DS are born to women aged <35 years despite having a lower chance of DS.
Recurrence in future pregnancies in parents of a child with standard trisomy 21 is 1%, or 1 in 100, until the maternal age-related chance is higher than 1%.[12] For mothers <30 years, the chance of recurrence is about 1.4%, and for those with advanced maternal age it is often most related to their current age. The reason for increased recurrence in women <30 years of age remains unclear but may be related to an age-independent increased chance of non-disjunction or a decreased likelihood of miscarriage of trisomic fetuses. For a child with translocation, the chance of recurrence for parents varies depending on the type of translocation. Parental chromosome karyotyping is obtained before providing recurrence estimates. Parents of a child with a de novo (sporadic) translocation have the same chance of recurrence as that of standard trisomy 21.[5][12] A father with a balanced translocation has a 3% to 5% chance of having a child with DS, and a mother with a balanced translocation has a 10% to 15% chance. If either parent carries the 21q21q translocation, the recurrence in future pregnancies is 100%.[5][12]
Pathophysiology
Humans typically have 23 pairs of chromosomes (46 total chromosomes). The first 22 pairs are called autosomes and are similar in males and females. The 23rd pair of chromosomes are called sex chromosomes because they determine sex. The nomenclature of human chromosomes for a male is 46,XY and female is 46,XX.[12]
Chromosomal findings in DS:
Standard trisomy 21
An extra chromosome 21 from meiotic non-disjunction or failure of the chromosome pairs to separate during gamete formation is present in about 95% of individuals with DS.[12] Population-based studies show that over 90% of non-disjunction errors leading to trisomy 21 occur in the oocyte and predominantly in maternal meiosis I.[10][11]
The chromosomal karyotype for standard trisomy 21 is indicated as 47,XY,+21 in males and 47,XX,+21 in females.
Robertsonian translocation
About 4% of individuals with DS have 46 chromosomes, one of which is a Robertsonian translocation between 21q and the long arm of one of the other acrocentric chromosomes (typically chromosome 14 or 21).[12] The translocation chromosome replaces one of the acrocentric chromosomes. The karyotype of a person with DS and a Robertsonian translocation between chromosomes 14 and 21 is indicated as 46,XX or XY, der(14;21)(q10;q10),+21.
Translocation DS has a relatively high chance of recurrence in families when one of the parents is a carrier of the translocation. For these reasons, chromosomal karyotyping of the parents is essential before providing potential recurrence estimates for future pregnancies.
A 21q21q Robertsonian translocation is a chromosome consisting of two chromosome 21 long arms. It is rare. In this case, all gametes of a carrier chromosome contain the 21q21q chromosome, with a double dose of chromosome 21q and a lack of any chromosome 21p genetic material. A carrier of 21q21q translocation will have a 100% recurrence rate of having a child with 21q21q translocation.[12]
Mosaic
About 1% of individuals with DS have mosaic type DS, with a cell population containing both typical and trisomy 21 karyotype. The phenotype is often believed to be milder than trisomy 21, but cognitive and behavioural profiles vary.
Virtually all individuals with DS have some characteristic facial features, a degree of intellectual disability, and hypotonia but these features vary in expression. The potential for medical complications also varies. Advances in genetics combined with using mouse models are important in understanding the genotype-phenotype relationship. Studies are focusing on how the genes on the trisomy part of chromosome 21 (HSA21) lead to DS. Animal models, particularly the trisomic mouse, are important in understanding the basic mechanism of gene dosage effects in DS. Ts65Dn mice are the most widely used models, as they are trisomic for nearly one half of the mouse-equivalent HSA21 genes.[13] Studies of these mouse models are examining the developmental and physiological processes, with the potential that these findings will translate to clinical relevance. Three hypotheses have been postulated:[14]
The gene dosage effect postulates that elevated expression of specific genes on HSA21 can be related to specific aspects of the phenotype.
The sensitisation model reveals that a specific phenotype occurs from one or a small set of triplicated genes.
The developmental instability hypothesis states that non-specific phenotypes arise from genetic imbalances due to the trisomy.
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