Letters to the Editor: Why are Children with Klinefelter Syndrome Tall?

Objective To evaluate the characteristics of glucose metabolism and the possible mechanisms of glucose metabolism disorder in patients with Klinefelter's syndrome (KS). Methods This was a retrospective clinical research. The following data were collected and analyzed: the general condition, gonadotropic and gonadal hormone levels, lipid and glucose profiles, glucose and insulin levels after a 75 g oral glucose tolerance test, and homeostasis model assessment of insulin resistance (HOMA-IR) in 19 patients with KS alone, 9 patients with both KS and DM, 18 DM patients without KS; all were hospitalized in PLA General Hospital since 1990. Independent sample t test was used for comparison betneen two groups. Results (1) The incidence of DM in KS patients was 32.1% (9/28); in patients with 47, XXY karyotype and 48, XXYY karyotype the incidence were 30.7% (8/26) and 50% (1/2), respectively; (2) Compared with simple KS patients, patients with both KS and DM was significantly older, while the testosterone (T) level was significantly lower[ (28±8) vs (22±4) year, (2.0±1.3) vs (5.4±4.3) nmol/L, t=3.044, -2.249; all P<0.05]; Although they had similiar fasting insulin level and area under the curve of insulin, KS patients complicated with DM presented a much higher insulin resistance index (6.5±3.4 vs 1.2±2.1, t=3.234, P<0.05) ; (3) KS patients complicated with DM were much higher and heavier than simple DM patients[(178±12)vs(170±6) cm, (91±23)vs(80±14)kg, t=0.750, 3.866; P<0.05]. The low-density lipoprotein concentration in patients with both KS and DM were lower than that of the patients with KS alone [(2.13±0.93)vs(2.85±0.50) mmol/L, t=-2.681; P<0.05], but their glucose and insulin levels during an oral glucose load were not different between two groups; (4) The estradiol-to-testosterone ratio of KS patients complicated with DM was significantly higher than that of simple KS patients as well as simple DM patients (t=2.302, 2.748; P<0.05) . Conclusions (1) KS patients tend to develop late-onset DM; (2) The possible risk factors of glucose metabolism disorder in KS patients are age, testosterone level, insulin resistance, high estradiol-to-testosterone ratio and abnormalities of X chromosome. Key words: Insulin resistance; Diabetes mellitus; Klinefelter's syndrome; X-chromosome; Testosterone

Insulin-like factor 3 (INSL3) is a peptide hormone produced in leydig cells of the testes. Its role in the adult male is unknown but INSL3 and its receptor RXFP2 have been linked to bone cell differentiation. It is speculated that low levels of INSL3 could be responsible for low bone mineral density in patients with primary osteoporosis and Klinefelter's Syndrome. The aim of this study was to assess plasma INSL3 in patients with osteoporosis and Klinefelter's Syndrome compared to healthy males. Fourteen healthy males, 21 males with osteoporosis (4 primary and 17 secondary) and 4 patients with Klinefelter's Syndrome were studied. Plasma INSL3, testosterone, LH, FSH and Sex hormone-binding globulin were evaluated. Plasma INSL3 concentrations were similar in osteoporosis patients compared to healthy controls (0.72 vs. 0.69 ng/mL, p = 0.26). INSL3 was significantly higher in patients with primary osteoporosis (n = 4) compared to age-matched healthy controls (n = 8) (0.845 vs. 0.665 ng/mL, p = 0.021). INSL3 levels in Klinefelter's Syndrome patients were significantly lower compared to healthy controls (0.39 vs. 0.69 ng/mL, p = 0.01). Plasma INSL3 levels were lower in Klinefelter's Syndrome reflecting testicular failure. INSL3 levels were not lower in men with osteoporosis. The relationship between INSL3, its receptor and bone metabolism requires further study.

Objective The clinical data of 4 cases of Klinefelter syndrome (KS) complicated with diabetes mellitus admitted to our hospital since 2016 were retrospectively analyzed in order to improve the understanding of the disease. Methods According to the records of inpatient and outpatient visits, the medical history and laboratory examination results of 4 KS patients with diabetes mellitus were summarized and analyzed. Results They were (43.0±12.7) years old, and were diagnosed with KS when they were (41.5 ± 13.9) years old. They were (1.67 ± 0.07) m tall. Their body mass index (BMI) was (22.05 ± 1.87) kg/m2. After the treatment, they got significant improvement in blood glucose and sex hormone levels (P 0.05). Conclusion Clinically, the early diagnosis rate of KS is low. Married adult male with infertility is an important clue for the diagnosis of KS. In addition to controlling blood glucose and androgen replacement therapy, risk factors such as dyslipidemia and fatty liver should be actively dealt with in KS patients with diabetes mellitus. Key words: Klinefelter syndrome; Diabetes mellitus; Karyotype

Background: Klinefelter syndrome may present as precocious puberty, which can be either central precocious puberty or peripheral precocious puberty, caused by an extragonadal germ cell tumor. Objective: Report two cases of Klinefelter syndrome that presented with precocious puberty due to a β-hCG producing mediastinal tumor. Method: Review of the clinical history, physical examination, and laboratory investigations. Results: Pseudo-precocity developed some years before diagnosis of -hCG producing tumor. The patients did not have typical physical features of this syndrome. The testes were small and had loose consistency. Conclusion: Klinefelter syndrome must be excluded in all boys presenting with precocious puberty due to a β-hCG producing tumor. Conversely, patients with Klinefelter syndrome should be regularly checked for β-hCG and α-fetoprotein levels. In those cases, the patients can be diagnosed and treated early. With the early treatment, they will be able to attain normal adult height and have fewer complications from the tumor.

To investigate the incidence of abnormal karyotypes and Y chromosome microdeletion in Chinese men with azoospermia, and the relationship with reproductive hormones. Four hundred and eighty nine cases of azoospermic patients and 20 fertile men were studied. Karyotypes and Y chromosome microdeletion were analyzed by G-banding and mutiplex polymerase chain reaction, respectively. Chemiluminescene immunoassay technique was applied to measure the serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), and prolactine (PRL). Chromosome abnormalities were found in 102 out of 489 azoospermic patients (20.86%), among them 86 (84.31%) cases had sex chromosome abnormalities, with 73 cases being Klinefelter syndrome. Y chromosome microdeletions were detected in 58 (11.86%) cases out of the 489 patients, and deletion of the AZFc region was the leading group (63.8% of all deletions), followed by AZFbc (19.0%), AZFabc (10.3%), AZFb or AZFa (3.4%). FSH, LH levels were significantly increased and T level was decreased in azoospermic patients compared with the fertile men group (P<0.01). Furthermore, in the azoospermic patients with Klinefelter syndrome or AZFabc microdeletions, FSH and LH levels were increased more significantly, and were statistically different from azoospermic patients with normal karotype or without Y chromosome microdeletion (P<0.05). In the Chinese men with azoospermia, the incidence of abnormal karyotype and Y chromosome microdeletion were similar to those described previously in other populations. In azoospermia with Klinefelter syndrome or AZFabc microdeletions, FSH and LH levels increased markedly indicating the protracted stimulation of gonadotrophs due to lack of androgen feedback.

Objective To explore the possibility of obtaining genetic offspring through emerging assisted reproductive technology in patients with nonmosaic Klinefelter syndrome. Methods The wife was primary infertility, with the right oviduct obstruction, the husband’s semen revealed no sperm, chromosome 47,XXY was diagnosed as Klinefelter syndrome. Assisted reproductive technology was required and sperm was successfully retrievaed through microdissection testicular sperm extraction (micro-TESE) on the day of his wife got oocytes picked up. Embryos were obtained by intracytoplasmic sperm injection (ICSI) technology. Results The sperm was successfully retrieved though micro-TESE and fertility rate was 76.19% (16/21) by ICSI. Six high-quality embryos and 7 blastocysts were retrieved. Clinical pregnancy was obtained after frozen-thawed embryo transfer. Conclusion Micro-TESE can become possible for patients with nonmosaic Klinefelter syndrome to produce their own genetic offsprings. Key words: Klinefelter syndrome; Microdissection testicular sperm extraction; Intracytoplasmic sperm injection

XYY syndrome, also named as super male syndrome, is the most common Y chromosome abnormality disease behind Klinefelter syndrome. The clinical phenotypes of XYY syndrome are quite different. The detection rate of XYY syndrome was low in the past, but with the development of prenatal diagnosis technics and the increasing attention paid by couples to the fetuses, the rate of prenatal diagnosis of fetal XYY syndrome is increasing. Currently, after the intrauterine diagnosis of fetal XYY syndrome, a multidisciplinary team is required to evaluate the prognosis of the fetus, and provide detailed and unbiased clinical consultations to the pregnant couples. After the birth of children with XYY syndrome, multidisciplinary team is still needed to carry out rehabilitation intervention and training for some children with XYY syndrome who have behavioral and cognitive problems. Assisted reproductive technology is needed to improve the pregnancy rate of patients with XYY syndrome and avoid adverse pregnancy outcomes. This article focuses on the latest research progresses in genetic background, diagnosis, fetal perinatal outcomes and postnatal survival, clinical phenotypes, evaluation and treatment of children with XYY syndrome, so as to provide clinical reference for childbearing couples who may be pregnant with children with XYY syndrome. Key words: XYY karyotype; XYY syndrome; Sex chromosome disorders, male; Diagnosis; Phenotype; Evaluation; Child

Mortality and cancer incidence were assessed in a cohort of 1373 patients with numerical sex chromosome abnormalities diagnosed at three cytogenetics centres in Britain during 1959-90, and were compared with expectations from national rates. Four hundred patients with Turner's syndrome were followed, of whom 62 died, with a relative risk (RR) of death of 4.16 (95% confidence interval (CI) 3.22-5.39). Turner's syndrome patients had greatly raised risks of death from diseases of the nervous, cardiovascular, respiratory, digestive and genitourinary systems. One hundred and sixty three deaths occurred among 646 patients with Klinefelter's syndrome with a 47,XXY constitution, giving an RR of 1.63 (1.40-1.91). Mortality in these patients was significantly raised from diabetes and diseases of the cardiovascular, respiratory and digestive systems. There was also significantly increased mortality for patients with X polysomy (RR = 2.11 (1.43-3.02)) and Y polysomy (RR = 1.90 (1.20-2.85)), the former with significantly increased mortality from cardiovascular disease and the latter from respiratory disease. The only significantly raised risks of cancer incidence or mortality in the cohort were for lung cancer and breast cancer in patients with Klinefelter's syndrome with a 47,XXY constitution, and non-Hodgkin's lymphoma in men with more than three sex chromosomes.

Metaphase chromosome analysis from cultured blood lymphocytes were investigated in 5,866 tests at Songklanagarind Hospital from 1990 through 2007 (18 years). Elaboration of G-bands by trypsin using Giemsa (GTG) was routinely employed with other banding techniques if required. High resolution chromosome banding was performed in suspected cases of structural chromosome abnormality. Successful studies were obtained in 5,665 tests (96.4 %) and 1,680 tests (28.7 %) were found to have chromosomal abnormalities. The failure rate was 3.4 % (201 tests). Fifty duplicated tests were discarded of the 1680 abnormal results, leaving 1,630 cases with abnormal chromosomes. Of 1,630 cases, Down, Edwards, and Patau syndromes were found in 933 (57.2 %), 87 (5.3 %) and 80 (4.9 %) cases, respectively. There were 215 cases with sex chromosome abnormalities (13.2 %), including 188 cases with Turner syndrome, 18 cases with Klinefelter syndrome, 6 cases with XXX syndrome and 3 cases with XYY syndrome. Androgen insensitivity syndrome (female with 46,XY) was found in 23 cases, and structural chromosome abnormalities were found in 222 cases (13.6 %). The remainder (70 cases/4.3 %) was composed of microdeletion, marker chromosome, fragile X syndrome and rare trisomy. To the best of our knowledge, this study is the largest group of chromosome analysis results reported from Thailand. These findings can be available to provide the database for genetic counseling.

Although chronic lung disease of various types has been associated with Klinefelter's syndrome, the incidence of chronic obstructive lung disease probably occurs more often than would be seen by chance alone. the mechanism of this association is obscure. the 2 patients reported herein had clinical and physiologic evidence as confirmation of chronic bronchitis, and one had postmortem evidences of chronic bronchitis. Both were markedly obese, and respiratory failure developed in both.

The shape and size of the craniofacial complex in 35 adults with Klinefelter syndrome (47,XXY) were analyzed cephalometrically and compared with 60 control males. Twenty-four angular and 18 linear measurements were obtained for each subject. The results showed that the 47,XXY males were different from the controls in several areas of the craniofacial skeleton. Most of the differences were located in the cranial base and the cranial base angle (p < 0.02). The length of the maxillary base was greater (p < 0.05) and more prognathic (p < 0.01) in the study group. The mandible was also longer and more prognathic (p < 0.01).

Objective To evaluate the therapeutic efficacy of two-stage tubularized transverse preputial island flapping for repairing disorders of sex development (DSD) with concurrent severe hypospadias. Methods From January 2012 to January 2016, retrospective analysis was performed for 87 DSD cases with concurrent severe hypospadias. The mean age of initial operation was 40 (10-182) months. Hypospadias types were shaft (n=1), penoscrotal (n=8) and perineal (n=78), including ovotesticular DSD (n=28), mixed gonadal dysgenesis (n=8), 5α-reductase deficiency (n=2), Klinefelter’s syndrome (n=2), androgen insensitivity syndrome (n=3) and perineal hypospadias (n=44). The procedures were single-stage Duckett alone (n=14), single-stage Duckett plus Duplay (n=21) and two-stage tubularized transverse preputial island flapping (n=52). Results The mean follow-up period was 2.7 (1.4-5.6) years. The complications of single-stage Duckett repair included fistula (2/14, 14.2%), stricture (1/14, 7.1%), urethral diverticulum (1/14, 7.1%); single-stage Duckett plus Duplay with fistula (6/21, 28.6%), urethral diverticulum (1/21, 4.8%) and stricture (2/21, 9.5%); two-stage tubularized transverse preputial island flap had fistula (4/52, 7.6%), stricture (1/52, 1.9%) and urethral diverticulum (2/52, 3.8%). Conclusions Two-stage tubularized transverse preputial island flapping is indicated for repairing DSD with concurrent severe hypospadias. There are low postoperative complication rates of urinary fistula, urethral stricture and diverticulum. Key words: Child; Urethroplasty; Disorders/Differences of sex developemt

Objective To describe different types of chromosomal abnormalities on male infertility.Methods From May 2006 to May 2012,2034 infertile males with genetic counseling underwent chromosome karyotype analysis,semen routine examination and reproductive hormones levels detection.The data from them were analyzed.Results 267 cases of chromosomal abnormalities were detected in 2034 cases (13.13％).258 cases underwent semen routine examination in 267 cases with chromosomal abnormalities,of which 190 cases of azoospermia,58 cases of oligozoospermia,10 cases of semen normal.In 267 cases of chromosomal abnormalities,including 169 cases (63.30％) of number abnormalities,mainly with azoospermia,157 cases of Klinefelter syndrome (KS) (58.80％),7 cases of 47,XYY (2.62％),4 cases of Turner syndrome (1.50％),1 case of marker chromosome (0.37％) ; 49 cases (18.35％) of structural abnormalities mainly with oligozoospermia,including 32 cases of chromosomal translocations (11.99％),17 cases of inversion (6.37％) ; 4 cases of sex reversal (1.50％) with azoospermia; 45 cases of chromosome polymorphism (16.85％) mainly with oligozoospermia.Non-mosaicism KS patients' age,testicular volume,semen volume,and serum reproductive hormones levels were compared between different groups of semen results,and there were no significant difference except age.Conclusions Chromosome abnormalities were the most important genetic causes of abnormal semen quality and male infertility.It is necessary to be performed chromosome karyotype analysis for infertile males. Key words: Chromosome aberrations; Semen quality; Male infertility

In infertile couples, a male contribution to infertility is found in 45-50%. The cause of male factor infertility remains largely unexplained, but varicocele and genetic disorder are recognized as major causes leading to spermatogenesis disability. Genetic disorder leads to male infertility include chromosomal abnormalities and Y chromosome microdeletions. Chromosomal abnormalities (numerical or structural abnormalities) can be detected routine karyotype analysis. In non-obstructed azoospemia (NOA) patients, the incidence of chromosomal abnormalities is about 15%, and Europe Association of Urology (EAU) recommend the karyotype analysis in men with azoospermia or oligozoospermia (sperm concentration <10 million/mL). The most common chromosomal aberration causing male infertility is 47, XXY, Klinefelter’s syndrome (KFS). In genetic disorder, dose the extra X chromosome play a most important role? In NOA patients, it’s true. But, in patients with severe oligozoospermia, Y chromosome microdeletions are the most major causes but they cannot be detected by routine karyotyping. Conventional diagnostic testing for the Y chromosome microdeletions is performed by PCR amplification of selected regions of the Y chromosome. Sequence tag site (STS) markers, which are specific for the loci, are amplified and the presence of the PCR products is detected by electrophoresis. Europe Andrology Association showed the guidelines for the diagnostic testing, and recommended six screening markers. In the past, we had used several STS markers including this recommended markers. But, the sensitivity of the recommended markers was insufficient for the Japanese population. To improve the sensitivity and specificity of the testing, we developed a new kit for the detection of molecular Y-chromosome deletions by re-selecting STS markers and carrying out multiplex target detection on the Luminex suspension array platform.In this session, I will introduce this kit in detail.

Azoospermia or the absence of sperm in semen is one of the sperm disorders that results in male infertility. There are two types of azoospermia, the first one isazoospermia caused by obstruction of the vas deferens (obstructive azoospermia) and the second one is azoospermia due to the damage of testes (nonobstructive azoospermia). The etiology of azoospermia could be genetic or non-genetic. Genetic factors may occur in genomics starting from chromosome until gene level or single nucleotide polymorphism (SNPs). At the chromosome level, there is Klinefelter’s syndrome (47, XXY) to the Y chromosome microdeletion, whereas at the gene level there is mutation of jsd, Bmp8b and other genes. At the level of SNPs, Genome Wide SNP Association Study (GWAS) had uncovered 20 SNPs which were related significantly to azoospermia. Extensive knowledge of genomics review on male infertility, is expected to promote the development of investigation and management of azoospermia.