XX male syndrome

Cytogenetic data obtained from investigating 1001 patients of Down syndrome (DS) and their parents over a period of 20 years (January 1979 - January 1999) are presented. The frequency of pure trisomy, mosaicism and translocation was 87.92, 7.69 and 4.39 per cent respectively. The origin of the extra chromosome 21 due to meiotic non-disjunction was 79.24 per cent maternal and 20.76 per cent paternal. A high frequency of acrocentric chromosome associations was also observed in mothers of children of Down syndrome, this might have predisposed to an enhanced risk for non-disjunction. Birth order of DS showed a higher number of first and second borns. Reproductive performances of the parents indicated a high rate of abortions, compared to controls. Cytogenetic investigations carried out over these years greatly helped in the management of these children and for counseling the affected families.

Key words Acrocentric - cytogenetic -Down syndrome - mosaicism - non-disjunction - translocation - trisomy

Down syndrome (DS) is a common autosomal genetic disorder with characteristic features, mental retardation and developmental delay. Its occurrence is about I in 700 births in the Western population'. In the Indian population its frequency is estimated to be 1 in 920 births2. The chromosomal investigations of patients of Down syndrome and their parents is essential and mandatory to establish the precise diagnosis for proper management and to assess the risk of recurrence in future pregnancies.

We present the cytogenetic findings on 1001 patients of Down syndrome, the largest number reported so far from the Indian sub-continent. The study was initiated to establish the frequency and distribution of types of Down syndrome and to determine the origin of the extra chromosome 21 from parental studies.

Material & Methods

Patients of Down syndrome referred to the Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad, for diagnostic confirmation and genetic advice over the past 20 years (January 1979January 1999) were included for study. During this period we investigated 1001 patients with Down syndrome. A complete clinical assessment, family history and pedigrees were all recorded in special case proformas. The age of the subjects ranged from newborns to 25 yr.

Cytogenetic investigations were carried out on peripheral blood lymphocyte microcultures according to a modified method of Moorhead et aP..GTG banding was performed according to Seabright', CBG banding according to Arrighi and Hsus and Silver staining (AgNOR) of nucleolar organizing regions according to Howell and Black. In each case 20 to 25 well spread metaphases were scored for the detection of chromosomal abnormality. In case of mosaicism, 50 or more metaphases were scored.

Parents of Down syndrome subjects were also investigated for chromosomal anomalies. The origin of extra chromosome 21 was detected by comparing the 21 chromosome polymorphisms of the parents and their DS children. The frequency and pattern of acrocentric chromosome associations were analysed in parents of Down syndrome according to the method of Zang and Back' to understand their role in the etiology of nondisjunction.

Statistical methods: Statistical analysis was carried out by Chi-square and Student's T test.

Results & Discussion

Cytogenetic analysis of 1001 cases of Down syndrome is presented in Table I. There were 880 cases of pure trisomy 21 (87.92%), 77 cases of mosaicism (7.69%) and 44 cases of translocation (4.39%). Male to female ratio in patients of Down syndrome was 1.41 : 1, as has been reported by Mutton et ale. In case of mosaicism the sex ratio was high (2.34 : 1 ).

The cytogenetic data of the present study compared with earlier reports from India and abroad" are shown in Table 11. From the pooled data, the frequency of pure trisomy 21 DS ranged from 80.05 to 97.8 per cent with a mean of 91.52 per cent, mosaic DS.ranged from 0.8 to 10.62 percent with a mean of 4.19 per cent and the frequency of translocation DS varied rom, 1.4 to 8.85 per cent with a mean of 4.23 per cent. In our study the frequencies of pure trisomy 21, mosaicism and translocation were 87.92, 7.69 and 4.39 per cent respectively. The higher incidence of mosaicism obtained in our study might be because of a thorough screening of a large number of metaphases.

Among the 44 translocation cases, the percentage of t(14;21) and mosaic t(14;21) were 45.45 per cent (n=20) and 4.54 per cent (n=2); t(15;21) and mosaic t(15;21) were 4.54 per cent (n=2) and 2.27 per cent (n=1); t(21;21) and mosaic t(21;21) were 36.36 percent (n=16) and 4.54 per cent (n=2) and t(21;22) was 2.27 per cent (n=1) respectively. Of the two mosaics with 46,XY/46,XY t(14;21), one case had maternal origin and the other originated de novo. For the case of 46,XY1 46,XY ((15;21) parental study was not possible and hence the origin could not be ascertained. Of the other two mosaics of 46,XY/46,XY t(21;21 ;21) one had maternal origin and for the other parental study was not possible.

Chromosomal investigations were performed on 445 parents of Down syndrome subjects. Parents of pure trisomy 21 (n=370) subjects and of mosaicism (n=45) showed normal karyotypes. Parents of translocation DS subjects (n=30) revealed carrier status in 4 mother's and one father. Three mother's were found to be carriers of t(14;21) in balanced state and one mother was a carrier of t(21;21). In one case both parents were found to be carriers of the translocated chromosome 14;21. Parental chromosomal analysis has great value in predicting the risk for future pregnancies. In case of t(21;21 ) if one paret`t is a carrier the chance of recurrence is .100 per cent. In case of the other translocations recurrence risk is below 10 per cent if one parent is a carrier.

The data pertaining to the parental ages of DS patients at the time of conception were recorded for 865 cases (Table HI). Maternal age at conception is an important factor in genetic counseling. Our attempts at obtaining these data from 865 cases revealed the birth of 89.74 per cent translocation Down children to mothers

Birth order of Down syndrome revealed a high frequency of first borns (29.71 %) followed by second borns (29.13%) and third borns (17.10%). A significantly (P

Andhra Pradesh is known for its high rate of consanguinity and early marriages. The present study provides a better sample to highlight the role of consanguinity in non-disjunction. Parental consanguinity was observed in 114 (13.18%) cases in parents of DS (n=865), whereas in the control population it was 196 (19.6%) out of 720. The data do not favour the role of recessive genes) in the predisposition of chromosome 21 to non-disjunction during gametogenesis and clearly shows the insignificant role of consanguinity in the etiology of DS.

Analysis of the parental origin of meiotic nondisjunction of chromosome 21 was possible only in 236 cases, 187 (79.24%) subjects received extra chromosome 21 from their mothers and 49 (20.76%) received it from their fathers. These data indicate clearly the major maternal contribution for the origin of pure trisomy 21. The acrocentric chromosome association (ACA) frequency and patterns in subjects of Down syndrome (n=236) and controls (n=200) is shown in Table IV We observed a significantly (P

A number of rare findings were seen in our series: (i) Familial transmission of 14;21 translocation - The mother had translocated chromosome in 100 per cent of her cells and the father showed mosaic pattern with normal cell line in 55 per cent of cells and translocated cell line in 45 percent of cells. History of consanguinity revealed first cousin relationship between them. Karyotypes of siblings showed mosaic translocation in two male sibs and normal chromosomal constitution in two female sibs.

(ii) Reproduction in Down syndrome - Reproduction in women affected with DS is rare. We have followed up a pregnant 21 yr old trisomy 21 woman during the course of our study. She gave birth to a normal male child with 46, XY chromosome complement. The child was born at full term and had normal birth weight of 2.8 kg.

(iii) Trisomy 21 associated with 47,XXY - The chromosomal constitution of the case was 47,XX + 21/ 47, XXY. Apart from the typical features of Down syndrome this case had features of ambiguity like enlarged clitoris, small penis and a simple urethral opening.

(iv) Trisomy 21 associated with D/D translocation This was a rare association detected.

In conclusion, our study based on a large sample shows the importance of chromosomal analysis for referred Down syndrome cases. Parental studies on 21 chromosome polymorphism helped us to evaluate the origin of extra chromosome 21. Increased frequency of associations among acrocentric chromosomes in parents of DS subjects might have predisposed. to an enhanced risk for non-disjunction. The findings of this study helped in managing DS children and counseling the affected families.

Acknowledgment

The authors are grateful to Prof. 0.S. Reddi, former Director, Institute of Genetics and Late Dr G.S. Isaac, Head, Division of Human Cytogenetics for providing the facilities to carry out this work. The technical assistance provided by Shriyuts M.P.R. Chary, C.S. Rao, K.S. Rao and G. Vigneshwar is acknowledged. The financial assistance provided by the University Grants Commission, New Delhi and Govt. of Andhra Pradesh, is acknowledged.

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A. Jyothy, K.S.D. Kumar, G.N. Mallikarjuna Rao, V. Babu Rao, M. Swarna, B. Uma Devi, M. Sujatha* C. Kusuma Kumari* & P.P Reddy**

Departments of Human Cytogenetics, *Clinical Genetics & **Environmental Toxicology, Institute of Genetics & Hospital for Genetic Diesases, Osmania University, Hyderabad

Accepted March 21, 2000

Accepted March 21, 2000

Reprint requests: Dr A. Jyothy, Head, Human Cytogenetics Division, Institute of Genetics, Osmania University Begumpet, Hyderabad 500016

Copyright Indian Council of Medical Research Apr 2000
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