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XY Female

Swyer syndrome, or XY gonadal dysgenesis, is a type of female hypogonadism in which no functional gonads are present to induce puberty in an otherwise normal girl whose karyotype is then found to be XY. Her gonads are found to be nonfunctional streaks. Estrogen and progesterone therapy is usually then commenced. The gonads are normally removed surgically because they do not function and may develop cancer. more...

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XY Female


The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation require the action of several genes, of which one of the earliest and most important is SRY, the "sex-determining region of the Y chromosome".

Mutations of SRY account for most cases of Swyer syndrome. When this gene is defective, testes fail to develop in an XY (genetically male) fetus. Without testes, no testosterone or antimullerian hormone are produced. Without testosterone the external genitalia fail to virilize, resulting in female genitalia. Without testosterone, the wolffian ducts fail to develop, so no internal male organs are formed. Without AMH the mullerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina).

A baby girl is born who is normal in all anatomic respects except that she has nonfunctional streak gonads instead of ovaries or testes. As girls' ovaries produce no important body changes before puberty, there is usually no suspicion of a defect of the reproductive system until puberty fails to occur.


Because of the inability of the streak gonads to produce sex hormones (both estrogens and androgens), most of the secondary sex characteristics do not develop. This is especially true of estrogenic changes such as breast development, widening of the pelvis and hips, and menstrual periods. Because the adrenal glands can make limited amounts of androgens and are not affected by this syndrome, most of these girls will develop pubic hair, though it often remains sparse.

Evaluation of delayed puberty usually reveals the presence of pubic hair, but elevation of gonadotropins, indicating that the pituitary is providing the signal for puberty but the gonads are failing to respond. The next steps of the evaluation usually include checking a karyotype and imaging of the pelvis. The karyotype reveals XY chromosomes and the imaging demonstrates the presence of a uterus but no ovaries (the streak gonads are not usually seen by most imaging). At this point it is usually possible for a physician to make a diagnosis of Swyer syndrome.


The consequences to the girl with Swyer syndrome of her streak gonads:

  1. Her gonads cannot make estrogen, so her breasts will not develop and her uterus will not grow and menstruate until she is given estrogen. This is often given through the skin now.
  2. Her gonads cannot make progesterone, so her menstrual periods will not be predictable until she is given a progestin, still usually as a pill.
  3. Her gonads cannot produce eggs so she will not be able to conceive children the natural way. A woman with a uterus but no ovaries may be able to become pregnant by implantation of another woman's fertilized egg (embryo transfer).
  4. Streak gonads with Y chromosome-containing cells have a high likelihood of developing cancer, especially gonadoblastoma. Rarely, this can begin as early as a few years of age, so the streak gonads are usually removed by surgery within a year or so after discovery of the diagnosis.


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Utility of XY-amelogenin gene primers for detection of sex chrommosomes
From Indian Journal of Medical Research, 4/1/98 by Chowdhury, Madhumita R

Madhumita R. Chowdhury, Roli Mathur & Ishwar C. Verma*

The utility of polymerase chain reaction (PCR) amplification of amelogenin gene as a reliable and rapid means of determination of sex chromosomes was tested in 20 patients of X-linked disorders (Duchenne muscular dystrophy, haemophilia and Wiscott-Aldrich and Hunter's syndromes), 12 of intersex (testicular feminization syndrome, male pseudohermaphrodites, true hermaphrodites) and 21 of congenital adrenal hyperplasia. Of these, 26 (49%) cases were for prenatal diagnosis of X-linked diseases and congenital adrenal hyperplasia (CAH). The presence of X and Y chromosomes was determined within 24 h of receiving the samples. The results were in conformity with cytogenetic studies in all instances. The analysis of amelogenin gene proved helpful in the diagnosis and management of these patients.

Keywords Amelogenin gene - intersex - karyotyping - ploymerase chain reaction - prenatal diagnosis - primers sex chromosomal disorders - X-linked diseases

Identification of the X and/or Y chromosome constitution is of great value in the diagnosis of sex chromosomal/intersex disorders, and for the prenatal diagnosis of diseases which are either X-linked or where the expression is sex dependent. The determination of sex chromosomes has been conventionally achieved by testing for X chromatin (Barr body)' and Y chromatin2. However, X chromatin is present only in a proportion of the cells and its interpretation is liable to error. The fluorescence of Y chromatin using quinacrine related dyes is not specific and can occasionally be observed in autosomes. Cytogenetic analysis/(karyotyping)3 is very accurate but is labour intensive and involves culturing of cells/ tissues. Fluorescent in situ hybridization4 (FISH) using probes specific to Y and X chromosomes is very accurate but requires expensive equipment and probes.

The presence of sex chromosomes can be demonstrated by molecular methods, either by using SRY or amelogenin gene probes'-7. Use of SRY probes gives a band only in the presence of Y chromosome, and the X chromosome remains unrecognized. Human amelogenin sequences are located on the distal short arm of the X chromosome in the p22.l -p22.3 region and near the centromere on the Y chromosome, possibly at the proximal long arm (Yg1 1) regions, at the pseudoautosomal boundary of the sex chromosomes. Apart from homology of about 90 per cent, the X chromosome amelogenin sequence has an additional 177 bp insert which permits the differentiation of X and Y chromosome specific bands. Nakahori et aP amplified the genomic DNA fragment coding for the amelogenin gene on the X and Y chromosomes and set the stage for their clinical use. We evaluated the utility of using amelogenin primers for detecting the presence of X and Y chromosomes.

Material & Methods

Materials : We studied 27 patients of sex chromosomal disorders and congenital adrenal hyperplasia (CAH), and foetuses of 26 pregnant women at risk for X-linked diseases. The selection of patients of CAH and intersex was consecutive while the patients with Turner's syndrome were selected randomly. This study was conducted during 1996-97 in the Genetics Unit, All India Institute of Medical Sciences, New Delhi.

Blood samples: Peripheral blood was collected in EDTA, from 12 patients with sex chromosomal disorders who were in the age group of 3 to 26 yr and from 15 CAH patients who were in the age group of newborn to 9 yr. DNA was extracted using the standard phenol/chloroform method'. Blood was also collected in heparin for culture to obtain karyotypes using the standard method3.

Chorionic villus/amniotic fluid samples : Samples were collected from 26 pregnant women who were in the age group of 21 to 36 yr. Chorionic villus samples (10-20mg) were collected in RPMI 1640 medium containing antibiotics and heparin from 25 pregnant women at 10-17 wk of gestation, 15 ml amniotic fluid was collected from I pregnant woman at 20 wk of gestation. DNA was then isolated using phenol/ chloroform method'. Culturing of chorionic villus was also carried out".

The extracted DNA was dissolved in sterile distilled water and quantified in a spectrophotometer (Pharmacia biotech.). PCR amplification was then carried out in MJ Research thermocyler using the following reagents standard lOX Taq polymerase buffer (containing 100mM Tris, pH 8.8: 15mM MgCI2, 500mMKC1, gelatin) (Bangalore Genei Pvt Ltd.), 1.25 mM dNTPs (Boehringer Manuheim. Germany). SpM of primers [F : TGA CCA GCT TGG TTC TA (A/T) CCC, R: CA (A/G) ATG AG (A/G) AAA CCA GGG TTC CA]. This particular sequence of amelogenin X-Y primers is siirhtll modified from that used by Nakahori et all 9. 'lese primers were a gift from Roger Mountford (St. Marv s Hospital, Manchester, UK], 2 units Taq polymerase enzyme (Bangalore Genei Pvt Ltd) and 0.5- i Kl*> template DNA. The cycling parameters were [mu]g for 4 min followed by 25 cycles of 94 deg C for I in in. 65oC for 30 sec, 720 deg C for 90 sec and a final extension at 72 deg C for 5 min. PCR products were then run on a 2 per cent agarose (FMC) gel, stained with ethidium bromide, and visualized under UV transilluminator (Vi(ber Lourmat) and photographed. The Fig. shows a representative gel.


The distribution of 27 patients in who;;1 X and ' chromosomes were analysed in peripherai blood samples is shown in Table 1. In all patients analysed the sex chromosomal constitution as determined by amelogenin gene-related PCR agreed with karyotype obtained after culturing. All these patients had ambiguous genitalia and determination of the presence of X and Y chromosomes helped to establish the proper diagnosis. In 15 patients suspected to have congenital adrenal hyperplasia the rapid diagnosis of female chromosomes in 14 enabled the institution of replacement therapy with corticosteriods.

The three patients of Turner's syndrome had karyotypes 45 X/46 X+mar, 46 X+mar and 45 XO/ 46 XY. PCR analysis showed that the marker was not a part of the Y chromosome in the first two patients, while in the third it confirmed the presence of the Y chromosome leading to appropriate management.

In the other patients of intersex PCR studies helped to quickly diagnose testicular feminization syndrome (4), male pseudo hermaphroditism (3) and true hermaphrodites (2) based on the identification of the sex chromosomes.

Table II depicts the use of amelogenin gene primers in chorionic villus and amniotic fluid samples for prenatal diagnosis of sex. In X-linked disorders the male foetus has a 50 per cent risk of being affected. Of the 20 cases of X-linked disorders, diagnosis of male karyotype in 10 led to further molecular studies to identify whether the foetus was affected with the specific disorder. In women with a history of previously having given birth to a child with congenital adrenal hyperplasia, diagnosis of female sex in 4 cases led to the institution of prenatal treatment with dexamethasone to prevent the development of ambiguous genitalia. In cases where a male foetus was diagnosed the use of corticosteroids was avoided.

In all cases of prenatal diagnosis follow up was done to confirm the sex at delivery and no discrepancy in diagnosis was found.


Analysis of Y chromatin or DNA studies of SRY gene reveals the presence of Y-chromosome material, indicating male sex. Diagnostic errors could ensue as these techniques do not detect the presence of X chromosome material. Therefore techniques which simultaneously detect X and Y chromosomes represent an improvement over those relying solely on the presence of the Y chromosome.

Diagnosis of chromosomal sex using amelogenin gene primers has proved valuable in the diagnosis and management of patients. In patients with ambiguous genitalia where no gonads are palpable the early determination of the sex of the child is important as in chromosomal females with virilization the commonest cause is congenital adrenal hyperplasia (CAH)'2. Thus in IS cases we were rapidly able to assign the correct sex, and initiate therapy with corticosteroids. In foetuses with CAH, virilization of the genitalia takes place in affected females. Therefore dexamethasone is given to the pregnant mothers to prevent intrauterine virilization. In such cases we were able to confirm the sex of the foetus at 10 wk of pregnancy by study of DNA from CV sample. This DNA was subsequently used for the prenatal diagnosis.

In Turner's syndrome although 45, XO is the most common karyotype, features of this syndrome are seen in cases with 45, X/46, XY mosacism or 46, X+mar karyotypes. It is crucial to know the origin of the marker chromosome because a gonad with Y chromosomal material has the potential to develop into a gonadoblastoma'3. A patient who was assumed to be pure 45, XO karyotype by the usual chromosome analysis, showed copies of Y chromosome by PCR testing. Therefore it is recommended that all patients of Turner's syndrome should be tested for the presence of Y chromosome by DNA technology.

In the other cases of intersex like testicular feminization syndrome and male pseudohermaphroditism, demonstration of X and Y chromosomes clarified the diagnosis and helped in genetic counselling and management. True hermaphrodities may have a testis on one side and a streak gonad on the other or they may have a vaginal pouch, or a cervical indentation which may be referred to as showing mixed gonadal dysgenesis. In such patients analysis of sex chromosomes is important as removal of the streak gonad is required if there is Y chromosome material.

In case of X - linked diseases like Duchenne's muscular dystrophy, haemophilia, and WiscottAldrich and Hunter's syndromes the male foetus has a 50 per cent risk of being affected. Therefore foetal sex is determined in the first trimester of pregnancy, and if confirmed to be male further molecular tests are done to determine disease status. Hence sex determination by PCR within 1-2 days of collection of the sample in such cases is very useful when time is a major constrain.

PCR using amelogenin gene primers has also been used to swiftly rule out maternal contamination in the tissue sample, identify incorrectly labelled samples from a husband and wife, or quantify the number of X and Y chromosomes by quantitative PCR.

In conclusion determination of sex chromosomes by PCR analysis of amelogenin gene primers is rapid and accurate and is valuable in molecular diagnostic service.


Authors thank the doctors and the obstetricians of the Genetics Unit and Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi for the collection of chorionic villus samples. The financial assistance provided by the Department of Biotechnology, New Delhi is gratefully acknowledged.


1. Verma RS, Babu A. Human chromosomes: Manual of basic techniques. New York : Pergamon Press Inc., 1989: 145-6. 2. Sumner AT, Evans HJ. Mechanisms involved in the banding of chromosomes with quinacrine and Giemsa. Exp Cell Res 1973; 81: 223-36.

3. Moorhead PS, Nowell PC, Mellman WJ, Battips DM, Hungerford DA. Chromosome preparations of leukocytes cultured from human peripheral blood. Exp Cell Res 1960; 20 : 613-6.

Wolman SR. Fluorescence in situ hybridization : a new tool for the pathologist. Hum Pathol 1994; 25 : 586-90. Nakagome Y, Seki S, Fukutani K, Nagafuchi S, Nakahori Y, Tamura T. PCR detection of distal Yp sequences in an XX true hermaphrodite. Am J Med Genet 1991; 41: 112-4.

Lau YF, Huang JC, Dozy AM, Kan YW. A rapid screening test for antenatal sex determination. Lancet 1984; i: 14-6. 7. Lo YMD, Patel P, Wainscoat JS, Sanpietro M, Gillmer MDG, Fleming KA. Prenatal sex determination by DNA amplification from maternal peripheral blood. Lancet 1989; ii: 1363-5. 8. Lau EC. Mohandas TK, Shapiro LJ, Slavkin HC, Snead MI. Human and mouse amelogenin gene loci are on the sex chromosomes. Genomics 1989; 4: 162-8. 9. Nakahori Y, Hamano K, Iwaya M, Nakagome Y. Sex identification by polymerase chain reaction using X-Y homologous primer. Am JMed Genet 1991; 39: 472-3.

10. Current protocols in molecular biology, vol. 1. New York: Greene Publishing Associates and Wiley - Interscience, 1992; 2.1.1-1.7.

11. Roy Chowdhury M, Mathur R, Prabhakara K, Singh G, Dubey S, Verma IC. Improved method for study of chromosomes of chorionic villus samples. Indian JMed Res 1996; 104: 26972.

12. New MI. Basic and clinical aspects of congenal adrenal

hyperplasia. J Steroid Biochem 1987; 27: 1-7. 13. Teter J, Boczkowski K. Occurrence of tumors in dysgenetic gonads. Cancer 1967; 20: 1301-10.

Department of Paediatrics, All India Institute of Medical Sciences, New Delhi

*Present address: Head. Department of Genetic Medicine, Sir Ganga Ram Hospital, New Delhi 110060

Reprint requests : Dr I.C. Verma, Senior Consultant and Head, Department of Genetic Medicine Sir Ganga Ram Hospital, Rajender Nagar, New Delhi 110060

Copyright Indian Council of Medical Research Apr 1998
Provided by ProQuest Information and Learning Company. All rights Reserved

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