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Journal of Medical Genetics, 1989, Vol. 26, 294-298

Fertility in a male with trisomy 21
From *the Paediatric Research Unit, .Division of Medical and Molecular Genetics, United Medical and Dental Schools of Guy's and St Thomas's Hospitals, London SE1 9RT; and #Cellmark Diagnostics, 1C1 Chemical Industries p1c, Blacklands Way, Abingdon, Oxfordshire 0X14 1DY.

SUMMARY We review the published reports on reproduction in cases of non-mosaic trisomy 21 (Down's syndrome) and present the first fully documented case of a non-mosaic male with Down's syndrome fathering a pregnancy, a fact which has important implications in the light of caring for these people in the community.

The Down's syndrome female has ovaries containing a reduced number of smaIl follicles, which have a greatly increased rate of atresia1. Twenty-six non mosaic trisomy 21 females, in 29 pregnancies, have produced 10 offspring with Down's syndrome, two spontaneously aborted fetuses whose status could not be evaluated, and 18 (including one monozygotic twin pair) chromosomally normal offspring. Of these; two are mentally retarded, four have other congenital malformations, and three were either spontaneously aborted or died of prematurity (table 1). Older published references describe a further seven women with nine offspring (table 2), although insufficient data are available to evaluate these.

Male Down's syndrome patients are often well masculinised, but are said to be infertile. Jagiello42 reported six adult male subjects showing normal serum testosterone levels in five of the six, normal testicular size in three, raised LH in five, and raised FSH in two patients. Benda43 commented that Down's syndrome males very often have small testes and that spermatogenesis was only rarely present. Stearns et al44 showed a complete absence of sperm in four out of nine patients and only occasional spermatozoa in the other five.

Histology performed on Down's syndrome testes usually shows markedly decreased spermatogenesis45. The inability of Down's syndrome males to reproduce may be related to their sexual impotence as well as to their inability to produce sufficient gametes.46

Mosaic Down's syndrome can be associated with fertility in the male, as the germ cell line can contain normal cells. Thompson,18 describing case 10 (table 1), states that "there appears to have been reason to believe that the father was also a mongol, but this cannot be confirmed". Other than this very brief anecdotal aside, we can find no reference in published reports to a non-mosaic male with trisomy 21 who has fathered a child.

Case report

Our patient is a 29 year old man with trisomy 21, showing some of the classical features of Down's syndrome: low intelligence, short stature, low set ears, epicanthic folds, large tongue, and clinodactyly. His mother was aged 24 at the time of his birth and he is the oldest of five sons.

He lives in special local authority housing with three other mentally retarded adults. He developed a relationship with a girl, living in the same house, who is educationally subnormal with no specific medical diagnosis. She had been on oral contraception, but had recently stopped this. The couple were referred after eight weeks of amenorrhoea. A singleton pregnancy was confirmed by ultrasound scanning.

They had had unprotected sexual intercourse for three months before they were seen in the clinic and it therefore seems likely that she conceived the pregnancy during her first unprotected cycle.

The couple were counselled in the presence of their social worker. They were toId that there was a significant risk of the haby being severely handicapped. They themselves decided that they would not want to bring up a handicapped child and that they wanted prenatal diagnosis.

All parties present agreed that the couple had understood the situation and that they had given informed consent:

TABLE 1 Reproduction in non-rnosaic Down's syndrome females.
No of


Refs Karotype of

Offspring where verified

Status of Offspring Presumptive father and 

Mental status where known

1 2 3   1 Normal female Patient´s father
2 4   2 Down´s syndrome male Mentally retarded; non-DS
3 5-7 47,XX,+21 3 Down´s syndrome female Patient´s father suspected
4 8 9 46,XY 4 Slight MR, suspected CHD Blind 60 year old epileptic (not MR) (normal 46,XY)
5 10   5 MR female; may represent "partial trisomy 21"; low nasal bridge Patient´s father suspected
6 11 12 46,XY 6 Normal male  
7 13   7 Normal male Mental debility?
8 14 15
8 Down´s syndrome male
9 Down´s syndrome female
Mother´s MR brother (46,XY)
Mother´s MR brother (46,XY)
9 16 17 46,XY 10 Apparently normal MZ male twins stillborn at 5 months Patient´s father (normal IQ)
10 18   11 Normal male Some suggestion that father was mongol; unsubstantiated
11 18 19   12 Macerated female fetus SA at 28 wk; status NK
13 Down´s syndrome male (TOP 20 wk)
12 20 46,XX 14 Normal female (v slight microcephaly)  
13 21 46,XX 15 3 months fetus, TOP post-SA. Status/sex not known
16 Normal female
14 22 47,XX,+21 17 Down´s syndrome female  
15 23 47,XX,+21 18 Down´s syndrome male MR but ? owing to brain damage
16 24 46,XX 19 Normal female  
17 24 46,XX 20 Normal female  
18 25 46,XY 21 Normal female Normal male
19 26 47,XX,+21 22 Down´s Syndrome female Tubercular invalid of 50+
20 27 46,XX 23 Normal female Patient´s husband (IQ=70)
21 28 47,XX,+21 24 Down´s syndrome male Patient´s husband; average IQ
22 29 46,XY+additional chromosome (3 different groups) in 4-4% of metaphases;
? Mosaic could not be confirmed
25 Normal male; missing L 5th finger; bilateral syndactyly of 2nd/3rd toes. Dermatoglyphics felt to be compatible with DS but mental development normal.Mosaicism would account for observed stigmata  
23 30 47,XX,+21 26 Down´s syndrome male  
24 31 46,XY 27 Normal male except for hypospadias. Low set ears, apparent bilateral syndactyly 2nd/3rd toes, subluxation of right hip Patient´s father
25 32 33 46,XY 28 Normal male karotype; multiple malformations: cleft palate, unilateral genu recurvatum. Died at 1 wk. Patient´s brother
26 34 46,XY 29 Normal male, born prematurely at 30 wk. Died at 1 d Patients uncle

A transcervical CVS was carried out.47 Unfortunately, some two weeks after the procedure, the woman experienced some bleeding, which settled on admission to hospital. However, the couple were sexually active throughout the post CVS period, and although this was found to exacerbate the bleeding, it was not possible to persuade them to cease. After further episodes of bleeding over the next six weeks, she lost the pregnancy some nine weeks after the CVS procedure.

Pathological examination (Dr M J Seller) showed a fetus of a physical size compatible with 16 to 17 weeks of gestation with no extemal or visceral anomalies.

Results and discussion

G banded chromosome analysis of the man showed a chromosome complement of 47,XY,+21 in 51 lymphocyte metaphases examined and in 101 meta-

TABLE 2 Very early reports of reproduction in Down's syndrome.
No Source Ref Karotype where known Status
1 Pogue (1917) 7 35
(a) SA 4-5 months
(b) Normal child, sex not known
2 Lind (1923)) 7 36 NK Caesarian section, status/sex NK
3 Weygandt (1936 7 37 NK Mother said to have had an abortive form of ´mongolism´. Pictures suggest ´mongolism´: fissured tongue, hyperextensible joints, low IQ. No further details of mother or child
4 Allen and Baroff (1955) 6 38 39   Describes 4 reports. Oster 39 says that diagnosis was uncertain in 2, Forsmann and Thysell 8 say that only 1 was convincing
5 Rosenberg (1924) 8 40 Normal
Married ´mongolian´women + 2 normal childrenNo further details known; Forsmann and Thysell 8 say diagnosis should be disregarded because he had unconventional views regarding ´transitional types of DS´
6 Hook (1949) 4 Non-mongol
Ana undisputed mongol, with typical facies and hand formations
7 Orel (1926) 4 41 Normal No further details

phases from a skin biopsy. His partner had a normal female 46,XX chromosome complement. Chromosome analysis, after chorionic villus sampling (CVS), showed the fetus to have a normal male chromosome complement (46,XY).

In order to confirm paternity, DNA 'fingerprint' patterns' 48 were analysed from the CVS sample and both parents.

DNA was digested with 80 units of HinfI for four hours at 37°C, run at 2.5 V/cm, in 0.7% aggarose until a 2-3 kbp marker had run 20 cm, then transferred to nylon membranes (Hybond-N, Amersham), and probed with probes 33-6 and 33-1549 (figure). The results from the two probes were combined to calculate the probability of the man with Down's syndrome being the true father of this pregnancy.

The number of bands recorded in the mother was 53, the same as the putative father. The number analysed in the fetus was 55. Of these 55, the number of bands shared with the mother was 32, and the number shared exclusively with the putative father was 22. In addition, there was one unassigned band. Therefore, the DNA 'fingerprint' of the fetus contained 23 non-matemal bands in the region analysed. Of these, 22 were found to have the same 'fingerprint' as the putative father.

These results provide three possible hypotheses.

(1) Paternity is correct and the undefined band is a new mutation of one of the parental bands; the probability for this is calculated to be 0-1978.

(2) The putative father is a first degree relative of the true father; the probability for this is 2-989x10-4.

(3) The putative father is unrelated to the true father, with a probability of 9-948x10-13.

We decided, therefore, that the last hypothesis can be rejected. The relative likelihood of hypotheses 1 and 2 is 661-8 to 1.

It is exceedingly unlikely that any of the man's relatives could be the father, and we therefore concluded that our patient was indeed the father of this pregnancy.

Further evidence of paternity was provided in a comparison of the cytogenetic analysis of the CVS sample and chromosomes from the father's blood. The QFQ staining technique was used to compare the chromosomes of our patient and the fetus. These showed similar looking intermediate (size three) Y chromosomes and a brilliant basal segment on the short arm of chromosome 22 (p11.20-p12.00 with intensity five).50

This would appear to be the first documented example of a pregnancy fathered by a male with apparently non-mosaic trisomy 21. Paternal mosaicism cannot, by definition, be excluded, but with 152 cells analysed a 2% mosaicism can be excluded with 95% confidence.51 lt may well be that an undetected normal cell line is responsible for this man's fertility, but from a practical cytogenetic viewpoint this mosaicism could not have been predicted before the pregnancy, and caution should therefore be exercised in advising people responsible for the care of adults with this condition about possible fertility.


This observation emphasises the need to maintain adequate contraceptive cover, especially as more mentally handicapped adults are removed from supervised institutions and encouraged to live within the community.

We would like to thank The Generation Trust and The Spastics Society for their financial support of the work which contributed to this paper. Mr Richard Sheridan is supported by a LORS grant, and Dr Juan Llerena Jr is supported by Action Research for the Crippled Child.

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