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Indian Journal for the Practising Doctor

Klinefelter Syndrome: Clinical Implications of Expanding Phenotype

Author(s): Rima Dada, Rakesh Kumar, M E Ahmad, Rajeev Kumar, RS Sharma, NP Gupta, A Mitra, Gupta SK, K Kucheria

Vol. 3, No. 6 (2007-01 - 2007-02)

Rima Dada, Rakesh Kumar, M E Ahmad, Rajeev Kumar, RS Sharma, NP Gupta, A Mitra, Gupta SK, K Kucheria

ISBN: 0973-516X

Rima Dada, MD, PhD (Associate Professor) and Rakesh Kumar (PhD Scholar) are from the Department of Anatomy, All India Institute of Medical Sciences, New Delhi-110029, India.
M E Ahmad is PDF, CWRU, Cleveland, Ohio,USA
Rajeev Kumar is Associate Professor, All India Institute of Medical Sciences, New Delhi-110029, India
R S Sharma is Chief, ART Centre, Army Research and Referral Hospital, New Delhi.
N P Gupta, M.S, M.Ch, FAMS, is Professor and Head, Department of Urology,
All India Institute of Medical Sciences, New Delhi-110029, India.
A Mitra (Research Associate) and S K Gupta (Chief, Gamete Antigen Laboratory) are from the National Institute of Immunology (NII), New Delhi.
K Kucheria, PhD, is Emeritus Medical Scientist,
All India Institute of Medical Sciences, New Delhi-110029, India

Corresponding Author: Dr Rima Dada, MD, PhD (Genetics), Associate Professor, Lab for Molecular Reproduction and Genetics, Department of Anatomy, AIIMS, New Delhi 29
Email: [email protected]


Chromsomal abnormalities are common in infertile men with an incidence of 5.8% as compared to 0.5% in the general population. Klinefelter syndrome is the commonest genetic cause of hypogonadism and infertility. The incidence of sex chromosome abnormalities is 1 in 400 births which include 47,XXY; 47,XXX and 45,X karyotypes. The addition of more than one extra X or Y chromosome occurs rarely. Many studies consider variants as a part of Klinefelter syndrome (KFS), but these cases have additional phenotypic anomalies and should be considered as a distinct entity. The phenotypic defect in 47,XXY is well known but in variant cases with polysomy of X and Y leads to additional features like cardiovascular, skeletal, behavioural, language and expressive and speech disorders. For these clinical problems therapy is available and early diagnosis and early androgen therapy facilitates better management of these cases. There is a direct correlation between the number of additional sex chromosome and severity of the phenotype. Therefore, in order to analyze these variant cases in detail this study was planned.

Key words: Klinefelter syndrome (KFS), Mosaic, Variants, Hypogonadism


Klinefelter’s syndrome is the most common genetic cause of male infertility, yet many cases remain undiagnosed because of substantial variation in clinical presentation. Early diagnosis and management with hormonal treatment can substantially improve the quality of life and prevent serious consequences. Sex chromosomal abnormalities occur in at least 1 in 400 births. One of the commonest chromosomal aneuploidy is Klinefelter Syndrome (KFS). KFS is the first human sex chromosomal abnormality to have been detected and is characterized by gynaecomastia, euchnoidism, small firm testes with hyalinization of seminiferous tubules, semeniferous tubular dysgenesis, androgen deficiency, hypergonadotrophic hypogonadism and azoospermia. This abnormality is the commonest cause of hypogonadsim and is associated with male infertility and cognitive defects. Its prevalence is 0.1% among infertile patients, up to 11% among the azoospermic, and 0.7% of oligozoospermics have 47,XXY chromosome complement. Of the 125 cases of male infertility referred to us, 44 were clinically diagnosed cases of KFS. We analyzed these 44 clinically suspected cases of KFS at the cytogenetic and molecular level using Fluorescent In situ Hybridisation (FISH) and found 14 cases with 47,XXY chromosome complement (KFS) and 23 cases with 46,XY/47,XXY karyotype. These cases were Klinefelter mosaics (KFM). Seven cases, which had additional cell lines, were classified as mosaic variants (KFV). These variant-cases showed additional clinical features, therefore they were studied in detail and their genotype was correlated with the phenotype.

Material and methods

Of the 125 cases of male infertility, 44 were clinically suspected cases of Klinefelter Syndrome and were referred to the infertility clinic of Urology and Endocrinology at the All India Institute of Medical Sciences. In each case a detailed clinical, reproductive and family history was taken and FSH, LH and testosterone levels were collected. Semen analysis was performed for assessing semen volume, pH, sperm count, viability, morphology, and motility as per the WHO guidelines (1999) (1). Testicular Fine Needle peripheral blood culture. Twenty-five well spread G-banded metaphases were karyotyped using Image Analysis System (Cytovision; Applied Imaging). In mosaic cases, 50 wellspread metaphases were analyzed. Fluorescent Aspiration Cytology (FNAC) was done whenever possible. Cytogenetic analysis was performed in each case by setting up In Situ Hybridization (FISH) was done following the standard protocol in 23 mosaic and 7 variant cases to identify any cryptic or low level mosaicism not detected cytogenetically. For FISH analysis, 200 interphase cells and 25 metaphase spreads were scored and the authors used CEP X and CEP Y fluorescent labeled probes. In the present paper, we discuss these cases with special emphasis on variant KF cases.

Klinefelter Syndrome

Of the 125 cases analysed cytogenetically 44 cases had KFS, of whom 14 had 47,XXY chromosome complement or were mosaics 46,XY/47,XXY-KFM (n=23) or variants KFV (n=7). The details of variant cases and comparison of KFV cases with the mosaic KFM and KFS cases have been tabulated (Tables 1 and 2).

Cases with 47,XXY Karyotype (KFS)

There were 14 cases with 47,XXY chromosomal complement, the mean age of whom was 25.6 years (range 20-35 years) and median height 170cm (range 158-188cm). Twelve cases had hypogonadism, two cases cryptorchidism and one case unilateral varicocele. Three of the 14 cases had micropenis while the rest had a normal phallus. Twelve cases exhibited poor development of secondary sexual characters; only two cases had well developed secondary sexual characters. Four cases had gynaecomastia. Seven cases had female habitus, while the other 7 had normal male habitus and were tall and thin. Of the 14 cases, 6 were mentally retarded while 8 cases had a normal intelligence quotient (IQ). Five cases showed behavioural abnormalities with severe temper tantrums and violent outbursts.

Three cases had speech abnormalities with difficulty in expressed speech. One case was impotent. All the fourteen cases were azoospermic (ie had complete absence of sperms in the semen). Thirteen cases had raised FSH levels while 1 case had decreased FSH level. In all the cases testosterone levels were low. Nine men were tall (>5 ft 8inch) and thin. Diabetes mellitus, anaemia and hepatitis B were found in 2 cases, one case had history of epileptic fits, while one case had asthma and recurrent episodes of upper respiratory infection. Testicular FNAC was done in 5 cases and showed ‘Sertoli Cell Only’ Type I syndrome (SCO Type I); in one case testicular biopsy showed hyalinization of the seminiferous tubules.

Table 1. Phenotypic Features in Men Mosaic Variants

Case No Karyotype Phenotype FSH mIU/ml LH mIU/ml T (ng/ml)
Case 1 47,XXY/
SCO, BL Small, biopsy cluster of leydig cells only. MVP, sm penis, fat, hair on body present M19, P21, MR 3.75 12 0.4
Case 2 46,XY(50%)/
48,XXYY (20%)
BL Small, Gyn Gr 3,Brest cancer small penis, no sec sex, low post. hair line, 5.8ft, M28, P30, speech abn, MR 24 36 2.8
Case 3 46,XY(53%)/
Thick BM, hyaline of ST (Biopsy), BL small testes, small penis, poor sec. sex, ASD, hypotonia, MR, no schooling d/t poor adj, temper, Speech abnormality, M33, P34 24 45 0.46
Case 4 47,XXY/
Sm, Tall 6.2, obese, Coxavalga, Gyn, low post. hair line, broad nasal bridge, coarse facial features 56.8 60 ND
Case 5 47,XXY (91%)/
48,XXXY (3%)/
48,XXYY (3%)/
46,XY (3%)
Hypogonadism, Atrophic, Prim. testicular failure, LoD, IQ less, poor in studies, MR, Gyn speech abn, 6 ft, M24,F30, micropenis, No sec sex 56 68 0.2
Case 6 47,XXY/
Hypogonadism. Poor development of secondary sexual characters, very tall, small penis, speech abnormal,,Pulmonary stenosis 44 38 0.4
Case 7 47,XXY/
Hypogonadism, poor dev. of seconadary sexual characters, slurred speech, congenital dislocation of hip, coarse facial features 32 40 0.2

Key: T3, T4, TSH: Thyroid hormones; ST: Seminiferous tubules; Dev: Development; d/t: due to; LoD: Lack of development; Gyn: Gynaecomastia; SSC: Secondary sexual characters; Sm: Small gonads; M: Maternal age; P: Paternal age; B/L: Bilateral; Lt: Left; Rt: Right; MR: Mental retardation; Crypt: Cryptorchidism; ND: Not detected; Abn: Abnormal; Adj: Adjustment; URI: Upper respiratory tract infection; Desc: Descended; IQ: Intelligence Quotient; DM: Diabetes mellitus; Temp exp: Temperature exposure; H/o: History of; Prim: Primary; Hyalin: Hyalinization of seminiferous tubules

Table 2. Distribution of Clinical Abnormalities in KFS, Mosaic KF and Mosaic Variants Cases

S. No. Features KFS n-14 KFM n-23 KFV n-7
1 Hypogonadism 12 17 6
2 Cryptorchidism 2 5 0
3 FNAC/ Biopsy-SCOI*/Hypospermatogenesis# 5* 1# 2*
4 Poor development of secondary sexual characters 12 12 6
5 Small penis 3 2 4
6 Impotent 1 0 0
7 Female habitus 7 1 0
8 Gynaecomastia 4 4 3
9 ALL/Radiotherapy 1 0 0
10 Mental Retardation/Poor in studies 6 1 4
11 Temper tantrums/Violent behaviour 5 1 1
12 Azoospermic 14 20 7
13 Oligozoospermic/ OAT 0 3 0
14 Congenital heart disease (CHD) 0 0 3
15 Delayed milestones 0 1 0
16 Low posterior hair line 0 0 2
17 Speech abnormality 3 0 5
18 Varicocele 1 0 0
19 Recurrent URI 1 1 0
20 Very Tall ≥5-8 9 12 6
21 Epileptic Fits 1 0 0
22 DM/Anaemia/Hepatitis B 2 1 0
23 High Temperature Exposure 0 2 0
24 Hypotonia 0 0 1
25 Skeletal abnormality 0 0 2
26 Normal FSH (1.2-5mIU/ml) 0 1 1
27 FSH raised 13 21 6
28 FSH low 1 0 0
29 Testosterone (2.7 –10.7ng/ml) 0 0 1
30 Testosterone low 13 22 6

Mosaic Klinefelter Cases (KFM) (46,XY/47,XXY)

There were 23 mosaic cases of Klinefelter syndrome with a mean age of 25.5 years. Seventeen cases presented with hypogonadism and 5 cases had cryptorchidism. Eleven cases had well developed and 12 cases poorly developed secondary sexual characters. Twelve patients were tall (height > 5’8”). Of the 23 cases, only four cases had gynaecomastia. Two cases had micropenis; in the vast majority (21) of the cases the phallus size was normal. One case had mental retardation and was poor at studies; he was violent at times with frequent adjustment problem with his peers. Twenty mosaic Klinefelter cases were azoospermic with no sperms in the semen and 3 were oligozoospermic. Of the latter, two had a high percentage of morphologically abnormal sperms with impaired motility and were oligoastheno- teratozoospermic (OAT). These cases had, respectively, 90%, 75% and 70% normal cell line. One case was a diabetic. Two cases had occupational exposure to high temperature; one of them was azoospermic and one had OAT. Twenty one cases had raised FSH levels, while two cases had FSH in the normal range. Decreased testosterone levels were detected in all the twenty three cases. Testicular FNAC was available in one case with 46,XY(90%)/47,XXY chromosome complement and showed hypospermatogenesis.

Variant Klinefelter

There were 7 mosaic variant Klinefelter cases with a mean age of 30.4 years. Six of them presented with hypogonadism and six had poor development of secondary sexual characters. Four cases had micropenis while the phallus was of normal size in three cases. All the 7 cases were azoospermic. The FSH levels were raised in 6 cases but within normal limits in 1 case. The testosterone levels too were low in 6 cases and in the normal range in one patient. Six of the 7 cases were tall (>5 ft 8 in). Two cases had a low posterior hair line. Three cases had gynaecomastia (figure 1) and one case was diagnosed with breast cancer. Of the 7 cases, 3 had, respectively, congenital heart disease with mitral valve prolapse (MVP), atrial septal defect (ASD) and pulmonary stenosis with pulmonary hypertension. One of the seven cases had coxa vara and thus difficulty in walking and one case had congenital dislocation of the hip (CDH) at birth. FNAC biopsy showed ‘Sertoli Cell Only’ Type 1 (SCO type I) Syndrome in one case and the presence of Sertoli cells and clumps of Leydig cells in one. Details of all the KFV (Klinefelter variants) cases are given in Table1.


In the present study there were a total of 44 cases of Klinefelter syndrome, of whom 14 had 47,XXY chromosomal pattern (KFS), 23 were mosaic Klinefelter (KFM) (47,XXY/46,XY) and 7 were mosaic variants. All these cases were analysed at cytogenetic and molecular cytogenetic level using FISH. FISH confirmed the presence and proportion of mosaic cell lines and also identified cell lines not detected by routine cytogenetic methods. This cell line was detected in interphase cells and thus helps in a better understanding of the phenotype and correlations with the genotype. Okada et al., (1999)(2) studied 148 patients with sterility caused by Klinefelter Syndrome and found 140 men with Klinefelter Syndrome and 8 men to be mosaic Klinefelter. The overall percentage of Klinefelter cases in the present study was 35.2% (44/125). This was much higher than that previously reported (3%)(3).

This higher prevalence may be due to the fact that AIIMS is a national-level tertiary referral hospital and therefore a high number of suspected KFS cases are referred to us for cytogenetic and molecular analysis. KFS is a leading genetic cause of male infertility. In the present study prevalence of KFS among azoospermic cases was 24.10%. This was higher than 11% reported by Nemeth et al, (2002)(4) but was consistent with the findings of Tournaye et al.,(1996) (5) who reported an incidence of 15-22% in azoospermic men. Okada et al (1999) reported a prevalence of 70.4% in azoospermics and De Braekleer and Dao in (1991)(6) a value of 10%. We found an incidence of 12.5% KFS among the oligozoospermic cases, which is much higher than that reported earlier (0.7%) by Nemeth et al, (2002)(4). This high percentage may be explained by the small number of cases oligozoospermia in our study. Although gynaecomastia has been reported previously in 50% of patients (Tournaye et al., 1996) (5) it was found in only 25% of our cases. One case with gynaecomastia had breast cancer. The incidence of breast cancer is increased by 50% in men with KFS. Median height and weight indicated that the patients were slightly taller and thinner than the average cytogenetically normal men of the same age. These findings are similar to those of Okada et al (1999) (2). Over 80% of our patients had small testes, 7 men had cryptorchidism of which 5 were mosaics (46,XY/47,XXY). Saragawa et al (1992) (7) reported an association between KFS and hypospadias and cryptorchidism. In the present study none of the KFS or KFM cases had hypospadias but seven cases had cryptorchidism. Nine cases had normal testis and 35 cases (79.8%) had small testis. These findings are slightly lower than those reported by Tournaye etal.,(1996) (5) , who reported small testes in 95% of the affected men. The mean age of the Klinefelter patients was 27.1 years in the present study which was lower than 32 years found by Okada et al (2). This may be because of an early age at marriage in India as compared to that in Japan as a result of which the cases report with infertility at an earlier age in India.

Semen analysis revealed azoospermia in all the 14 cases of KFS, 20 cases of mosaic Klinefelter and 7 mosaic variants. Three mosaic cases with 30%, 15% and 10% 47,XXY cell line showed oligozoospermia. One of the mosaic cases worked in a rubber preparation factory and was exposed to high temperature which might have led to a high percentage of sperms with morphological abnormalities and impaired motility.(8) Testicular fine needle aspiration cytology (FNAC) showed hypospermatogenesis in this case. Though KFS is associated with a testicular phenotype of hyalinization of seminiferous tubules and semeniferous tubular dysgenesis this case showed hypospermatogenesis. This may be due to the presence of 90% normal cell line, 46,XY.

Though KFS is associated with azoospermia, recent studies (5,9) have reported spermatogenesis in mosaic cases. Two cases showed OAT though one of them had no exposure to high temperature. Okada et al., (1999) (2) also reported a high percentage of sperms with morphological abnormalities especially round and elongated spermatids in KFS subjects. In the present study, there were majority of sperms with amorphous head (22%), coiled tail (38%), and tapered head (15%).

Pubic hair distribution and euchnoid habitus was seen in 8 of the 44 cases. Okada et al (1999) (2) reported euchnoid habitus and female pattern of hair distribution in one third of the studied cases. Half of the patients in their study had low testosterone concentrations with elevated gonadotrophins while 50% had normal concentrations of testosterone. In the present study, however, we found low testosterone levels in the majority (93.2%) of cases; normal testosterone level was found only in one case. Of the 44 cases, gonadotrophins (FSH and LH) were elevated in 40 (90.9%) of cases, low in one case and within the normal range in three cases.

Two mosaic variants had low posterior hair line which has not been reported earlier in KF cases. The percentage of mosaicism detected by G banding and FISH was almost identical after scoring 200 interphase cells and 25 metaphase spreads. In one case FISH detected an additional cell line of 50,XXXXYY which was not detected cytogenetically. Thus FISH helps in detection of cryptic and low level mosaicism and is an important adjunct to conventional cytogenetics. FISH is a highly sensitive, efficient, accurate and reproducible technique that can be used independently for screening of aneuploidies. (10,11)

Azoospermia is not a consistent feature of KFS. Beregere et al in 2002 (9) found that 47,XXY subjects showed germinal aplasia while 46,XY/47,XXY mosaics focally showed spermatogenesis but Tournaye et al (1996) (5) found foci of spermatogenesis in some 47,XXY cases. Four out of 8 47,XXY subjects showing spermatogenesis were reported by Bergere et al (2002)(9). In the present study, 3 mosaic cases had oligoasthenoteratozoospermia and 1 case showed hypospermatogenesis. But two cases had high percentage (64% and 83%) of sperms with abnormal morphology and impaired motility and one case had oligozoospermia.

Sparkes et al., (1973) (12) and Foresta et al., (1999) (13) also reported a number of cases of KFS who had succeeded in fathering a child before the era of Assisted Reproduction. One case with 47,XXY chromosome complement had acute lymphocytic leukemia (ALL). Patients with KFS are known to be at an increased risk of malignant tumours(14) . Three variant mosaic cases, respectively, had congenital heart disease with mitral valve prolapse (MVP), atrial septal defect (ASD) and pulmonary stenosis with pulmonary arterial hypertension. Congenital heart defects have been reported in mosaic variant Klinefelter cases in earlier studies (15). These cardiovascular anomalies were not observed in KFS or KFM cases but three Klinefelter variants had cardiovascular anomalies. The presence of 48,XXYY and 49,XXXYY cell line probably led to the development of this cardiovascular defect. Studies have found that the greater the aneuploidy the more severe is the clinical manifestation of the disorder (16) . One KFS case had a history of epileptic fits since birth. Earlier tonic clonic seizures and epileptiform electroencephalograms (EEGs) were reported in 12 cases of KFS (16). Neurological deficit and seizures have also been reported by Tournaye etal.,(1996) (5) in KFS cases.

Twenty five percent (11/44) cases were found to have a low IQ in the present study, 17% also had behavioural problems and had violent temper outbursts. A higher risk of learning disabilities, cognitive deficit, and behavioural and psychiatric disorders exist in KFS, mosaics and mosaic variants. Linden et al., (1995) (17) and Kruse et al.,(1998) (18) reported that mental capability diminishes directly with the number of extra X chromosomes and IQ reduction of 15 to 16 points occurs with addition of each extra X chromosome.

One case with KFS and 3 variant mosaics had slurred speech and difficulty in expressive language. Linden et al., (1995) (17) concluded that language is also directly affected by the number of extra X chromosomes. Expressive and receptive language are both severely affected in men with extra X chromosome and this may lead to violent temper outbursts (16,17) . One variant mosaic was found to have hypotonia. Low muscle tone and muscular incoordination has been previously reported by Linden et al.,(1995) (17) who found that coordination is affected by extra genetic material. One mosaic variant case had coxa valga since birth and another variant case had congenital dislocation of hip (CDH). Skeletal anomalies like radioulnar synostosis, coxa valga and vara have been reported previously in KFV (15,17).

In addition there were 2 cases, one KFM and one KFS case with diabetes mellitus and one case with hepatitis B also had KFS. Two cases, one KFM and one KFS, had recurrent episodes of upper respiratory tract infection and asthma. Takeuchi et al., (1999) (19) reported a case of KFS with mixed connective tissue disease and diabetes mellitus. Mulliez et al., (1986) (20) reported respiratory disorders in 47,XXY subjects.

The pentasomy (49,XXXYY) and tetrasomy (48,XXYY) are two of the rarest sex chromosome defects occurring with an estimated incidence of 1 in 85,000 and 1 in 50,000 male births respectively.(21) In the curent study we had 7 variant cases and these cases had additional phenotypic features, cardiovascular and skeletal abnormalities, and severe mental retardation. Sex chromosomal polysomy is associated with pre- and postnatal growth deficiency, severe mental retardation, hypogenitalism, and skeletal, facial and cardiovascular anomalies. Linden et al (1995) (17) suggested that polysomy X and Y may lead to cognitive and behavioural problems which, in turn, might affect somatic development. The addition of a single X to an XY karyotype results in semeniferous tubule dysgenesis. Additional X and Y chromosome result not only in infertility but also in hypoplastic and malformed external genitalia. Three mosaic KF cases in our study had oligozoospermia. The presence of germ cells could probably be because of the normal cell line being the major cell line in these cases. Estop et al ( 1998)(22) and Foresta et al (1999)(13) suggested that in mosiac KF cases, germ cells may achieve meiosis and may produce mature spermatozoa. Accordingly, such cases from our study were made aware of the Assisted Reproductive Technology (ART) and were counselled to go in for case they opted for ART. All the variant cases had strikingly elevated gonadotrophins indicating markedly severe testicular damage due to the presence of extra genetic material and all were azoopsermic.

One of the cases (Case 2) presented with marked gynaecomastia. KF cases with gynaecomastia have been reported to have an increased risk of breast cancer (23).

One KFV case (Case 3) had a relatively milder phenotype with no cardiovascular or skeletal abnormality. The lesser severity of manifestation could be due to the presence of normal cell line compared to a male with pure polysomy X or Y and relatively few clinical manifestation. But the patient had an aggressive disposition with a low IQ. Abnormal behaviours and temper tantrums have been reported in sex chromosomal aneuploides in early studies (17).

A direct correlation between testicular function and FSH level is well established(24). The increase in FSH levels is a reliable indicator of testicular damage. However testicular FNAC of Case 1 showed Sertoli Cell Only Syndrome Type I indicating severe testicular damage although FSH and LH levels were within the normal range. The present finding stresses on the need of FNAC in such cases.

The present study highlights substantial variability in variant cases due to genetic heterogeneity. Molecular cytogenetic analysis also aids in a better understanding of the genotype-phenotype correlation by identifying cell lines not identified cytogenetically. Generalization of these mosaic cases is not possible and they should not be confused with classical KFS cases with 47,XXY karyotype. Detailed clinical, genetic evaluation should be undertaken and genetic counseling offered with early treatment to get better results by androgen therapy and psychological help.

Our study suggests that a larger number of cases needs to be analysed at both cytogenetic and molecular level to be able to appreciate the variability of phenotype and its correlations with the genotype. That will facilitate provision of suitable genetic counseling, early treatment, and better management of such cases.


Authors thank the Indian Council of Medical Research (ICMR) for the financial support.


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