A female prevalence among patients suspected clinically to have DS but without T21was documented in a chapter titled “Gender affects clinical suspicion of Down syndrome” in 2011. Since then no further studies followed probably because such patients have routinely been taken for carriers of undetected mosaicism due to either its very low level or the presence in other tissues unavailable for cytogenetic testing. Current report is intended to explain the difference between the mentioned patient cohorts

• Down syndrome • Mosaic trisomy 21 • Advanced maternal age • Sex ratio • False-positive diagnoses

Kovaleva NV (2026) Neglected Phenomenon: Female Predominance in Clinically Diagnosed Down Syndrome. J Neurol Disord Stroke 13(1): 1247

T21: Trisomy of chromosome 21; AMA: Advanced maternal age; DS: Down sydrome

Down syndrome (DS) is one of the most common indications for cytogenetic testing. In most cases the clinical diagnosis is confirmed by the presence of an additional chromosome 21 (trisomy 21, T21). Three features have been established, a strong association of free trisomy 21 frequency with advanced maternal age (AMA), a predominance of males among carriers of non-mosaic T21, and a predominance of females among carriers of mosaic T21.

One more phenomenon, a female predominance among patients with clinical suspicion of DS but without T21was described in the chapter “Gender affects clinical suspicion of Down syndrome” in 2011 [1]. This chapter has been downloaded approximately 5,000 times, but no further research has been conducted on this topic. The most likely explanation is that such patients were commonly assumed to be carriers of undetected mosaicism either due to its very low level or due to its presence in other tissues inaccessible for cytogenetic testing.

In an earlier study of the same population the AMA rate in mosaicism carriers was 41.6% versus 32.3% in nonmosaic patients [2]. Later, Joan Morris, using data 

from the National Down Syndrome Cytogenetic Register in Egland and Wales, stated that the maternal age distribution in trisomy 21 with mosaicism differed from that in nonmosaic trisomy 21. Approximately two-thirds of trisomy 21 with mosaicism appeared to have the same age-related risks as nonmosaic trisomy 21, while one-third appeared to be independent of maternal age [3].

It has been widely accepted that mosaicism occurs in a very low proportion of T21 carriers, around 1-2% [4]. A more detailed analysis of data from eleven large (over 1000 DS patients diagnosed postnatally) population-based studies revealed variation in this proportion, ranging from 0.8% in Kuwait [5] to 3.9% in St. Petersburg, Russia [2]. Presumably, this variation can be explained by the required number of the cells evaluated. The average figure for over 34,000 patients is 2.2% of all free T21 carriers.

Data from the New York State Chromosome Registry on over 10,000 cases of Down syndrome [6] confirmed the data from England and Wales Cytogenetic Register [7] that in mosaic Down syndrome DS the male/female ratio (SR, sex ratio) is less than 1.0 (SR=0.8 and 0.9, respectively) as opposed to the ratio in nonmosaic cases which is close to 1.2. A recent study showed a chromosome-specific female predominance of trisomy mosaics in both prenatal and postnatal diagnoses, including mosaics for trisomy 21 with SR=0.73 and SR=0.8, respectively [8].

Summing up the above, one may conclude that the characteristics of patients with clinical suspicion of DS but with normal karyotype differ from those of patients with mosaicism. Their proportion among patients tested for T21 is significantly higher than that of patients with mosaiciss, and the prevalence of females is higher as well (Tables 1 and 2).

Table 1: Accuracy of the clinical diagnosis of Down syndrome in neonates *

Table 2: Accuracy of the clinical diagnosis of Down syndrome in patients of various ages *

Furthermore, according to Kovaleva [1], the proportion of AMA among false positive neonates is 7.5% which is not different from the general population (6% to 9% per year) which suggests that this clinical essence is not age-dependent unlike to mosaicism carriers.

Unfortunately neither detailed clinical description of false-positive patients nor follow-up studies have been conducted. The author hopes to draw attention to this phenomenon and uncover its genetic basis.

1. Kovaleva NV. Gender affects clinical suspicion of Down syndrome. 2011; 13: 203-216.
2. Kovaleva NV, Butomo IV, Körblein A. Studies in patients with confirmed trisomy 21. 2001; 35: 43-49.
3. Morris JK. Trisomy 21 mosaicism and maternal age. 2012; 158A: 2482-24844.
4. Hultén MA, Jonasson J, Iwarsson E, Uppal P, Vorsanova SG, Yurov YB, et al. Trisomy 21 mosaicism: we may all have a touch of Down syndrome. 2013; 139: 189-192.
5. Al-Awadi SA, Krishna Murthy DS, Farag TI. Cytogenetic profile of DS in Kuwait. 1994; 77: 7.
6. Hook EB, Cross PK, Mutton DE. Female predominance (low sex ratio) in 47,+21 mosaics. 1999; 84: 316-319.
7. Mutton D, Alberman E, Hook EB. Cytogenetic and epidemiological findings in Down syndrome, England and Wales 1989 to 1993. 1996; 33: 387-394.
8. Kovaleva NV, Cotter PD. Mosaicism for autosomal trisomies: Comprehensive review of the literature suggests inverse effects of carriers’ gender and maternal age on clinical manifestations. 2024; 7: 116-124.