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1.
Orv Hetil. 2018 Jul;159(27):1121-1128. doi: 10.1556/650.2018.31081.

[Examination of sex chromosome abnormalities in childhood].

[Article in Hungarian; Abstract available in Hungarian from the publisher]

Author information

1
II. Gyermekgyógyászati Klinika, Semmelweis Egyetem, Általános Orvostudományi Kar Budapest, Tűzoltó u. 7-9., 1094.

Abstract

INTRODUCTION:

Early diagnosis of sex chromosome abnormalities is important because of prevention, family planning and optimal therapy.

AIM:

Investigation of the relationship between phenotype, age at time of diagnosis and therapeutic options in sex chromosome aberrations.

METHOD:

Processing data of 51 children with sex chromosome abnormalities who were diagnosed between 2009 and 2014 and examined at the 2nd. Department of Pediatrics, Semmelweis University, by the methods of anamnesis, family tree analysis, physical examination, karyotype analysis and fluorescent in situ hybridisation.

RESULTS:

41% of the patients were diagnosed with Turner-, 18% with Klinefelter-, 10% with double-Y-, 6% with triple- and poly-X-syndrome, 19% with other gonadal dysgenesis and 6% with other abnormality. The average age at diagnosis: Turner- and Klinefelter-syndrome 10 years, other gonadal dysgenesis 9 years, 46,XX,t(X;10) 17 years, other abnormalities 1-2 years.

CONCLUSIONS:

Numerical aberrations of the sex chromosomes are more common than structural aberrations. Klinefelter-, triple- and poly-X-syndromes are underdiagnosed in childhood. Early diagnosis of Turner-syndrome and other gonadal dysgenesis is necessary to optimise therapy and prevent associated diseases. This can be achieved by modern prenatal diagnostic methods and targeted activity of family pediatricians. Orv Hetil. 2018; 159(27): 1121-1128.

KEYWORDS:

citogenetika; cytogenetics; disorders of sex development; nemi fejlődés zavarai; nemi kromoszómaaberrációk; sex chromosome aberrations

PMID:
29961370
DOI:
10.1556/650.2018.31081
[Indexed for MEDLINE]
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2.
Endocr Dev. 2018;33:149-157. doi: 10.1159/000487531. Epub 2018 Jun 8.

Fertility Preservation in Klinefelter Syndrome Patients during the Transition Period.

Abstract

Spermatozoa have occasionally been identified in ejaculate of adult Klinefelter syndrome (KS) patients but very exceptionally in KS adolescents. Spermatozoa can also be retrieved in testicular tissue of KS adolescents. The testis may also harbor spermatogonia and noncompletely differentiated germ cells. Neither clinical features nor hormonal parameters could predict germ cell recovery in KS adults or adolescents. No predictive factors can actually demonstrate that early diagnosis of KS would allow increasing the chance of sperm retrieval even if it has been suggested that semen quality may decline with age in KS patients. Leydig cell dysfunction may also be another factor that might affect the spermatogenesis process in XXY adolescents. Fertility preservation might be preferentially proposed in KS adolescents when semen sampling is possible, when the patient is able to consider alternative options to become a father, and to accept germ cell retrieval failure. However, precocious diagnosis of KS has also to be considered because it might not solely improve the possibility of fertility preservation after the onset of puberty, but also the medical care and the quality of life of these patients.

PMID:
29886483
DOI:
10.1159/000487531
[Indexed for MEDLINE]
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3.
Cancer Radiother. 2018 May;22(3):255-263. doi: 10.1016/j.canrad.2017.10.006. Epub 2018 Apr 16.

Metastatic mediastinal mature teratoma with malignant transformation in a young man with an adenocarcinoma in a Klinefelter's syndrome: Case report and review of the literature.

Author information

1
Radiotherapy department, centre Paul-Strauss, Unicancer, 3, rue de la Porte-de-l'Hôpital, 67065 Strasbourg cedex, France.
2
Genetics department, centre Paul-Strauss, Unicancer, 3, rue de la Porte-de-l'Hôpital, 67065 Strasbourg cedex, France.
3
Spine surgery department, hôpitaux universitaires de Strasbourg, 1, place de l'Hôpital, 67091 Strasbourg cedex, France.
4
Pathology department, hôpital Hautepierre, 1, avenue Molière, 67098 Strasbourg cedex, France.
5
Thoracic surgery department, hôpitaux universitaires de Strasbourg, 1, place de l'Hôpital, 67091 Strasbourg cedex, France.
6
Pediatric oncohaematology department, hôpital Hautepierre, 1, avenue Molière, 67098 Strasbourg cedex, France.
7
Radiotherapy department, centre Paul-Strauss, Unicancer, 3, rue de la Porte-de-l'Hôpital, 67065 Strasbourg cedex, France; Laboratory EA 3430, Translational medical federation, université de Strasbourg, 67000 Strasbourg, France. Electronic address: gnoel@strasbourg.unicancer.fr.

Abstract

Malignant transformation of mediastinal mature teratoma is extremely rare and worsens the prognosis of the disease. Transformation can appear synchronously to or several years after the initial diagnosis. Clinical and radiological signs can orientate the clinician but the definitive diagnosis is obtained thanks to histology. An 11 year-old boy presented with a mediastinal mature teratoma and bone and pulmonary metastases. He received six cycles of chemotherapy combining etoposide, ifosfamide, cisplatin, followed by resection of a 16×14×9cm mediastinal mass. Karyotype analysis revealed the presence of an additional sex chromosome X (47 XXY) pathognomonic of Klinefelter's syndrome. Ten years later, sciatalgia revealed malignant transformation of a pre-existing sacral bone metastasis into gastrointestinal adenocarcinoma. The patient received four cycles of chemotherapy combining oxaliplatin, 5-fluorouracil and cetuximab. This treatment was followed by a complete resection of the sacral metastasis and completed with adjuvant irradiation of 54Gy in 30 daily fractions. Twelve months after the diagnosis of relapse, the patient remained alive without disease. To our knowledge, this is the first case of adenocarcinoma developed in bone metastases of a mediastinal mature teratoma in a boy with a Klinefelter's syndrome. We propose a review of the literature and an analysis of 20 others published cases of mediastinal teratoma with malignant transformation into adenocarcinoma.

KEYWORDS:

Germ cell tumour; Klinefelter's syndrome; Mature mediastinal teratoma; Metastasis; Métastases; Syndrome de Klinefelter; Teratoma with malignant transformation; Tumeur germinale; Tératome avec transformation maligne; Tératome mature du médiastin

PMID:
29673950
DOI:
10.1016/j.canrad.2017.10.006
[Indexed for MEDLINE]
Icon for Elsevier Science
4.
Ital J Pediatr. 2018 Apr 3;44(1):43. doi: 10.1186/s13052-018-0485-x.

A Klinefelter boy with congenital adrenal hyperplasia: too much or too little androgens?

Author information

1
Department of Pediatrics, Institute for Maternal and Child Health IRCCS, "Burlo Garofolo", Via dell' Istria 65/1, Trieste, Italy. giagiada@gmail.com.
2
University of Trieste, Trieste, Italy. giagiada@gmail.com.
3
Department of Pediatrics, Institute for Maternal and Child Health IRCCS, "Burlo Garofolo", Via dell' Istria 65/1, Trieste, Italy.
4
University of Trieste, Trieste, Italy.

Abstract

BACKGROUND:

The simultaneous occurrence of Klinefelter Syndrome (KS) and Congenital Adrenal Hyperplasia (CAH) is an exceptional event: there are just three case reports (two children and a 51 years old man) describing males affected by both KS and 21OHD (21-hydroxylase deficiency) CAH, the first causing androgen deficiency, the latter leading to androgen excess.

CASE REPORT:

We report the 4th case of association of KS and CAH in a young man with CAH with good androgen control and with normal secondary sex characteristics, whose Klinefelter syndrome was diagnosed because of reduced testicular volume. He was the first reported case of association of KS and CAH who started androgen replacement therapy in the pubertal age and whose pubertal development was described and followed up step by step.

CONCLUSION:

In a boy with CAH and small testicular volume, it's important to consider that hypogonadism may be masked by the adrenal androgens excess and a karyotype should be performed once testicular adrenal rests have been ruled out.

KEYWORDS:

Congenital adrenal hyperplasia; Hypogonadism; Klinefelter

PMID:
29615074
PMCID:
PMC5883637
DOI:
10.1186/s13052-018-0485-x
[Indexed for MEDLINE]
Free PMC Article
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5.
Andrologia. 2018 Jun;50(5):e13004. doi: 10.1111/and.13004. Epub 2018 Mar 7.

Klinefelter syndrome and fertility-Impact of X-chromosomal inheritance on spermatogenesis.

Author information

1
Department of Obstetrics and Gynaecology, Radboudumc Nijmegen, Nijmegen, The Netherlands.
2
Department of Obstetrics and Gynaecology, University Hospital Münster, Münster, Germany.
3
Department of Human Genetics, Radboudumc Nijmegen, Nijmegen, The Netherlands.
4
Department of Urology, Radboudumc Nijmegen, Nijmegen, The Netherlands.

Abstract

With the use of testicular sperm extraction (TESE), spermatozoa can be retrieved in about 30%-50% of men with Klinefelter syndrome (KS). The reason for the absence or presence of spermatozoa in half of the men with KS remains unknown. Therefore, the search for an objective marker for a positive prediction in finding spermatozoa is of significant clinical value to avoid unnecessary testicular biopsies in males with (mostly) low testicular volume and impaired testosterone. The objective of this study was to determine whether paternal or maternal inheritance of the additional X-chromosome can predict the absence or presence of spermatogenesis in men with KS. Men with KS who have had a testicular biopsy for diagnostic fertility workup TESE were eligible for inclusion. Buccal swabs from nine KS patients and parents (trios) were taken to compare X-chromosomal inheritance to determine the parental origin of both X-chromosomes in the males with KS. Spermatozoa were found in TESE biopsies 8 of 35 (23%) patients after performing a unilateral or bilateral TESE. Different levels of spermatogenesis (from the only presence of spermatogonia, up to maturation arrest or hypospermatogenesis) appeared to be present in 19 of 35 (54%) men, meaning that the presence of spermatogenesis not always yields mature spermatozoa. From the nine KS-trios that were genetically analysed for X-chromosomal inheritance origin, no evidence of a correlation between the maternal or paternal origin of the additional X-chromosome and the presence of spermatogenesis was found. In conclusion, the maternal or paternal origin of the additional X-chromosome in men with KS does not predict the presence or absence of spermatogenesis.

KEYWORDS:

TESE ; 47,XXY; Klinefelter syndrome; andrology; genetics

PMID:
29512178
DOI:
10.1111/and.13004
[Indexed for MEDLINE]
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6.
Cytogenet Genome Res. 2017;153(4):190-197. doi: 10.1159/000487039. Epub 2018 Feb 22.

Clinical, Hormonal, and Genetic Evaluation of Idiopathic Nonobstructive Azoospermia and Klinefelter Syndrome Patients.

Author information

1
Laboratory of Medical Genetics, Medical Research Institute, Dankook University College of Medicine, Seoul, Korea.

Abstract

To investigate the clinical, hormonal, and genetic factors in infertile men with idiopathic nonobstructive azoospermia (NOA) or azoospermic Klinefelter syndrome (KFS), a total of 556 and 96 patients, respectively, were included in this study. All patient samples were analyzed cytogenetically. Serum reproductive hormone levels were measured. Microdeletions in the azoospermia factor (AZF) region of the Y chromosome were detected by multiplex PCR using 16 specific sequence-tagged sites. FSH and LH levels in both NOA and KFS patients were significantly higher than the normal range, and the testosterone level in KFS patients was significantly lower. Ninety-two (95.8%) of the KFS patients showed non-mosaic 47,XXY karyotypes and 47,XXY,inv(9)(p11.1q13); the other KFS patients had mosaic karyotypes of 47,XXY/46,XY, 47,XXY/46,XX, and 47,XXY/48,XXXY/46,XX. Among the 556 idiopathic NOA patients with normal karyotypes, 67 (12.05%) had microdeletions in the AZF region of the Y chromosome. Microdeletions were most frequently detected in the AZFc region, followed by AZFa, AZFb, AZFbc, and partial AZFc deletions. However, Y chromosome microdeletions were not found in any of the azoospermic KFS patients. In view of the hormonal and genetic abnormalities in infertile men with idiopathic NOA and with azoospermic KFS, genetic testing for karyotype, Y chromosome microdeletions, and hormonal parameters is advocated.

KEYWORDS:

Idiopathic nonobstructive azoospermia; Karyotype; Klinefelter syndrome; Reproductive hormones; Y chromosome microdeletions

PMID:
29466784
DOI:
10.1159/000487039
[Indexed for MEDLINE]
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7.
Acta Med Okayama. 2018 Feb;72(1):61-66. doi: 10.18926/AMO/55664.

Slow Fetal Heart Rate before Miscarriage in the Early First Trimester Predicts Fetal Aneuploidy in Women with Recurrent Pregnancy Loss.

Author information

1
Department of Obstetrics and Gynecology, Okayama University Graduate Schools of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.aisakamoto@cc.okayama-u.ac.jp.

Abstract

Establishing whether miscarriages result from fetal aneuploidy or other factors is important for treating recurrent pregnancy loss. We examined the relationship between fetal heart rate (FHR) before miscarriage in the early first trimester and fetal karyotype, analyzing 223 pregnant women with recurrent pregnancy loss. Among the pregnancies, 110 resulted in live births regarded as normal karyotype (the Norm-group). The other 113 pregnancies ended in miscarriage, and we categorized them into groups based on fetal karyotype, determined by chorionic villus sampling: the Misc-NK (normal karyotype) group, n=35 euploid cases; the Misc-CA1 (chromosomal abnormality) group, n=18 cases of aneuploidy with trisomies 13/18/21, Turner's syndrome, or Klinefelter's syndrome; and the Misc-CA2 subgroup, n=60 cases of other aneuploidies excluding those in the Misc-CA1 group. We compared the groups' regression line slopes and intercepts for FHR by an analysis of covariance. The FHRs of the Norm, Misc-NK and Misc-CA1 groups increased from 36 to 49 days after fertilization, but did not significantly differ across these groups. The Misc-CA2 group's FHR did not increase and significantly differed from the other three groups (p<0.01). These results suggest that the absence of an increase in FHR in early pregnancy may indicate the presence of chromosomal abnormalities causing miscarriage.

KEYWORDS:

chorionic villi; aneuploidy; fetal heart rate; recurrent pregnancy loss

PMID:
29463940
DOI:
10.18926/AMO/55664
[Indexed for MEDLINE]
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8.
Eur J Endocrinol. 2018 Apr;178(4):343-352. doi: 10.1530/EJE-17-0902. Epub 2018 Jan 25.

Endocrine and metabolic evaluation of classic Klinefelter syndrome and high-grade aneuploidies of sexual chromosomes with male phenotype: are they different clinical conditions?

Author information

1
Section of Medical Pathophysiology and EndocrinologyDepartment of Experimental Medicine, Sapienza University of Rome, Rome, Italy matteo.spaziani@uniroma1.it.
2
Section of Medical Pathophysiology and EndocrinologyDepartment of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Abstract

OBJECTIVE:

Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in males. As well as classic KS, less frequent higher-grade aneuploidies (HGAs) are also possible. While KS and HGAs both involve testicular dysgenesis with hypergonadotropic hypogonadism, they differ in many clinical features. The aim of this study was to investigate the endocrinal and metabolic differences between KS and HGAs.

DESIGN:

Cross-sectional, case-control study.

METHODS:

88 patients with KS, 24 with an HGA and 60 healthy controls. Given the known age-related differences all subjects were divided by age into subgroups 1, 2 and 3. Pituitary, thyroid, gonadal and adrenal functions were investigated in all subjects. Metabolic aspects were only evaluated in subjects in subgroups 2 and 3.

RESULTS:

FT4 and FT3 levels were significantly higher in HGA than in KS patients in subgroups 1 and 2; in subgroup 3, FT4 was significantly higher in controls than in patients. Thyroglobulin was significantly higher in HGA patients in subgroup 1 than in KS patients and controls. Hypergonadotropic hypogonadism was confirmed in both KS and HGA patients, but was more precocious in the latter, as demonstrated by the earlier increase in gonadotropins and the decrease in testosterone, DHEA-S and inhibin B. Prolactin was significantly higher in HGA patients, starting from subgroup 2. Total and LDL cholesterol were significantly higher in HGA patients than in KS patients and controls, while HDL cholesterol was higher in controls than in patients.

CONCLUSIONS:

KS and HGAs should be considered as two distinct conditions.

PMID:
29371337
DOI:
10.1530/EJE-17-0902
[Indexed for MEDLINE]
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9.
Int J Med Sci. 2018 Jan 1;15(1):31-35. doi: 10.7150/ijms.21075. eCollection 2018.

Next Generation Sequencing expression profiling of mitochondrial subunits in men with Klinefelter syndrome.

Author information

1
Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina (EN), Italy.
2
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Abstract

Objectives: Klinefelter syndrome (KS) is one of the most common sex-chromosome disorders as it affects up to 1 in every 600-1000 newborn males. Men with KS carry one extra X chromosome and they usually present a 47,XXY karyotype, but less frequent variants have also been reported in literature. KS typical symptoms include tall stature, gynecomastia, broad hips, hypogonadism and absent spermatogenesis. The syndrome is also related to a wide range of cognitive deficits, among which language-based learning disabilities and verbal cognition impairment are frequently diagnosed. The present study was carried out to investigate the role of mitochondrial subunits in KS, since the molecular mechanisms underlying KS pathogenesis are not fully understood. Methods: The study was performed by the next generation sequencing analysis and qRT-PCR assay. Results: We were able to identify a significant down-expression of mitochondrial encoded NADH: ubiquinone oxidoreductase core subunit 6 (MT-ND6) in men with KS. Conclusion: It is known that defects of the mtDNA encoding mitochondrial subunits are responsible for the malfunction of Complex I, which will eventually lead to the Complex I deficiency, the most common respiratory chain defect in human disorders. Since it has been shown that decreased Complex I protein levels could induce apoptosis, wehypothesizethat the above-mentioned MT-ND6 down-expression contributes to the wide range of phenotypes observed in men with KS.

KEYWORDS:

Klinefelter syndrome; MT-ND6; NGS analysis; cognitive deficits; qRT-PCR.

PMID:
29333085
PMCID:
PMC5765737
DOI:
10.7150/ijms.21075
[Indexed for MEDLINE]
Free PMC Article
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10.
Hormones (Athens). 2017 Jul;16(3):313-317. doi: 10.14310/horm.2002.1741.

Identification of an AR mutation in Klinefelter syndrome during evaluation for penoscrotal hypospadias.

Author information

1
Department of Pediatric Endocrinology, Dokuz Eylul University, Faculty of Medicine, Narlıdere, İzmir, 35340, Turkey.
2
Department of Pediatric Genetics, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey.
3
Department of Medical Genetics, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey.
4
Department of Medical Genetics, Ege University Faculty of Medicine, Izmir, Turkey.
5
Department of Pediatric Endocrinology, Dokuz Eylul University, Faculty of Medicine, Narlıdere, İzmir, 35340, Turkey. ayhanabaci@gmail.com.
6
Department of Pediatric Genetics, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey. ayhanabaci@gmail.com.

Abstract

Genital anomalies, ranging from female genitalia to milder degrees of undervirilization, are rarely reported in Klinefelter syndrome, in which a male is classically expected to be born with male external genitalia. Though androgen insensitivity syndrome (AIS) is one of the possible pathogenic mechanisms also in Klinefelter syndrome with genital anomalies, to date the AR gene has not been analyzed in any of the published cases of Klinefelter syndrome of the milder phenotype, except for those patients presenting with a severe phenotype, such as female external genitalia.Lack of interest in considering androgen insensitivity in Klinefelter syndrome with a milder phenotype of genital anomalies may impede its identification through an accurate diagnosis. We present a 14-month-old boy with penoscrotal hypospadias, micropenis, and a ventral penile chordee abnormality who was observed to have both a 47,XXY karyotype and a known missense mutation in the ARgene that was inherited from his mother. Although it is recommended that Klinefelter syndrome be considered in the differential diagnosis of penoscrotal abnormalities, mutations in specific genes involved in androgen synthesis or responsiveness should also be investigated.

PMID:
29278518
DOI:
10.14310/horm.2002.1741
[Indexed for MEDLINE]
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11.
Am J Obstet Gynecol. 2017 Dec;217(6):691.e1-691.e6. doi: 10.1016/j.ajog.2017.10.005. Epub 2017 Oct 13.

Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
2
Baylor Genetics, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
3
Baylor Genetics, Baylor College of Medicine, Houston, TX.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX.
5
Baylor Genetics, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX. Electronic address: breman@bcm.edu.

Abstract

BACKGROUND:

Since its debut in 2011, cell-free fetal DNA screening has undergone rapid expansion with respect to both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this screening tool, both for the originally included common autosomal and sex-chromosomal aneuploidies as well as the more recently added chromosomal microdeletion syndromes, have lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations of this screening tool to inform pre- and posttest counseling, pre/perinatal decision making, and medical risk assessment/management.

OBJECTIVE:

The objective of this study was to determine the positive predictive value and false-positive rates for different chromosomal abnormalities identified by cell-free fetal DNA screening using a large data set of diagnostic testing results on invasive samples submitted to the laboratory for confirmatory studies.

STUDY DESIGN:

We tested 712 patient samples sent to our laboratory to confirm a cell-free fetal DNA screening result, indicating high risk for a chromosome abnormality. We compiled data from all cases in which the indication for confirmatory testing was a positive cell-free fetal DNA screen, including the common trisomies, sex chromosomal aneuploidies, microdeletion syndromes, and other large genome-wide copy number abnormalities. Testing modalities included fluorescence in situ hybridization, G-banded karyotype, and/or chromosomal microarray analysis performed on chorionic villus samples, amniotic fluid, or postnatally obtained blood samples. Positive predictive values and false-positive rates were calculated from tabulated data.

RESULTS:

The positive predictive values for trisomy 13, 18, and 21 were consistent with previous reports at 45%, 76%, and 84%, respectively. For the microdeletion syndrome regions, positive predictive values ranged from 0% for detection of Cri-du-Chat syndrome and Prader-Willi/Angelman syndrome to 14% for 1p36 deletion syndrome and 21% for 22q11.2 deletion syndrome. Detection of sex chromosomal aneuploidies had positive predictive values of 26% for monosomy X, 50% for 47,XXX, and 86% for 47,XXY.

CONCLUSION:

The positive predictive values for detection of common autosomal and sex chromosomal aneuploidies by cell-free fetal DNA screening were comparable with other studies. Identification of microdeletions was associated with lower positive predictive values and higher false-positive rates, likely because of the low prevalence of the individual targeted microdeletion syndromes in the general population. Although the obtained positive predictive values compare favorably with those seen in traditional screening approaches for common aneuploidies, they highlight the importance of educating clinicians and patients on the limitations of cell-free fetal DNA screening tests. Improvement of the cell-free fetal DNA screening technology and continued monitoring of its performance after introduction into clinical practice will be important to fully establish its clinical utility. Nonetheless, our data provide valuable information that may aid result interpretation, patient counseling, and clinical decision making/management.

KEYWORDS:

47,XXX; 47,XXY; 47,XYY; NIPT; amniocentesis; cell-free DNA; microdeletion syndrome; noninvasive prenatal screening; noninvasive prenatal testing; prenatal diagnosis; trisomy 13; trisomy 18; trisomy 21

PMID:
29032050
DOI:
10.1016/j.ajog.2017.10.005
[Indexed for MEDLINE]
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12.
J Clin Res Pediatr Endocrinol. 2018 Jun 1;10(2):100-107. doi: 10.4274/jcrpe.5121. Epub 2017 Oct 12.

Klinefelter Syndrome in Childhood: Variability in Clinical and Molecular Findings

Author information

1
Near East University Faculty of Medicine, Department of Pediatric Endocrinology, Nicosia, Cyprus
2
İstanbul University İstanbul Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey
3
University of Kyrenia Faculty of Medicine, Department of Pediatric Endocrinology, Kyrenia, Cyprus

Abstract

OBJECTIVE:

Klinefelter syndrome (KS) is the most common (1/500–1/1000) chromosomal disorder in males, but only 10% of cases are identified in childhood. This study aimed to review the data of children with KS to assess the age and presenting symptoms for diagnosis, clinical and laboratory findings, together with the presence of comorbidities.

METHODS:

Twenty-three KS patients were analyzed retrospectively. Age at admission, presenting symptoms, comorbid problems, height, weight, pubertal status, biochemical findings, hormone profiles, bone mineral density and karyotype were evaluated. Molecular analysis was also conducted in patients with ambiguous genitalia.

RESULTS:

The median age of patients at presentation was 3.0 (0.04-16.3) years. Most of the cases were diagnosed prenatally (n=15, 65.2%). Other reasons for admission were scrotal hypospadias (n=3, 14.3%), undescended testis (n=2, 9.5%), short stature (n=1, 4.8%), isolated micropenis (n=1, 4.8%) and a speech disorder (n=1, 4.8%). The most frequent clinical findings were neurocognitive disorders, speech impairment, social and behavioral problems and undescended testes. All except two patients were prepubertal at admission. Most of the patients (n=20, 86.9%) showed the classic 47,XXY karyotype. Steroid 5 alpha-reductase 2 gene and androgen receptor gene mutations were detected in two of the three cases with genital ambiguity.

CONCLUSION:

Given the large number of underdiagnosed KS patients before adolescence, pediatricians need to be aware of the phenotypic variability of KS in childhood. Genetic analysis in KS patients may reveal mutations associated with other forms of disorders of sex development besides KS.

KEYWORDS:

Ambigious genitalia; cryptorchidism; disorders of sex development; speech impairment

PMID:
29022558
PMCID:
PMC5985377
DOI:
10.4274/jcrpe.5121
[Indexed for MEDLINE]
Free PMC Article
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13.
Genetics. 2017 Dec;207(4):1621-1629. doi: 10.1534/genetics.117.300382. Epub 2017 Oct 11.

Long-Term Fragility of Y Chromosomes Is Dominated by Short-Term Resolution of Sexual Antagonism.

Author information

1
Department of Biology, Texas A&M University, College Station, Texas 77843 coleoguy@gmail.com.
2
College of Biological Sciences, University of Minnesota, St. Paul, Minnesota 55108.

Abstract

The evolution of heteromorphic sex chromosomes has fascinated biologists, inspiring theoretical models, experimental studies, and studies of genome structure. This work has produced a clear model, in which heteromorphic sex chromosomes result from repeated fixations of inversions (or other recombination suppression mechanisms) that tether sexually antagonistic alleles to sex-determining regions, followed by the degeneration of these regions induced by the lack of sex chromosome recombination in the heterogametic sex. However, current models do not predict if inversions are expected to preferentially accumulate on one sex-chromosome or another, and do not address if inversions can accumulate even when they cause difficulties in pairing between heteromorphic chromosomes in the heterogametic sex increasing aneuploidy or meiotic arrest. To address these questions, we developed a population genetic model in which the sex chromosome aneuploidy rate is elevated when males carry an inversion on either the X or Y chromosome. We show that inversions fix more easily when male-beneficial alleles are dominant, and that inversions on the Y chromosome fix with lower selection coefficients than comparable X chromosome inversions. We further show that sex-chromosome inversions can often invade and fix despite causing a substantial increase in the risk of aneuploidy. As sexual antagonism can lead to the fixation of inversions that increase sex chromosomes aneuploidy (which underlies genetic diseases including Klinefelter and Turner syndrome in humans) selection could subsequently favor diverse mechanisms to reduce aneuploidy-including alternative meiotic mechanisms, translocations to, and fusions with, the sex chromosomes, and sex chromosome turnover.

KEYWORDS:

Genetics of Sex; Y chromosome loss; aneuploidy; inversion; pseudoautosomal region; sex chromosome; sexual antagonism

PMID:
29021279
PMCID:
PMC5714469
DOI:
10.1534/genetics.117.300382
[Indexed for MEDLINE]
Free PMC Article
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14.
Genet Mol Res. 2017 Sep 27;16(3). doi: 10.4238/gmr16039780.

Down-Klinefelter syndrome (48,XXY,+21) in a neonate associated with congenital heart disease.

Author information

1
XY Diagnose Laboratório de Biotecnologia, , Brasil mauricioassis@hotmail.com.
2
UTI Neonatal Nicola Albano, , Brasil.
3
XY Diagnose Laboratório de Biotecnologia, , Brasil.
4
Faculdade de Medicina, , , Brasil.
5
, , Brasil.

Abstract

Double aneuploidy is considered a rare phenomenon. Herein, we describe a case of double aneuploidy 48,XXY,+21 in a neonate with congenital heart defects. The 28-day-old neonate male (23-year-old mother and 24-year-old father) was admitted to a neonatal intensive care unit owing to congenital heart disease. Echocardiography showed a complete atrioventricular septal defect with Rastelli type B and significant left ventricular failure, moderate atrioventricular valve regurgitation, right-sided heart failure, and preserved systolic function. Cytogenetic analysis of the newborn showed double aneuploidy 48,XXY,+21. The maternal karyotype was 46,XX,inv(9)(p11q13) and the paternal was 46,XY. Characteristics associated with Down syndrome are observed in newborns; on the other hand, children under 10 months of age and neonates may show little or no signs of the Klinefelter syndrome. According to this study, there seem to be differences between the frequency of congenital heart disease among patients with Down-Klinefelter and Down syndrome. At about 11 months of age, the child died after undergoing heart surgeries. The early cytogenetic study is important for better diagnosis and management of the disease.

PMID:
28973759
DOI:
10.4238/gmr16039780
[Indexed for MEDLINE]
15.
J Korean Med Sci. 2017 Nov;32(11):1848-1851. doi: 10.3346/jkms.2017.32.11.1848.

Hypogonadism Makes Dyslipidemia in Klinefelter's Syndrome.

Author information

1
Department of Urology, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
2
Department of Gynecology and Obstetrics, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
3
Department of Urology, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea. jtandro@cgh.co.kr.

Abstract

Klinefelter's syndrome (KS) is a genetic syndrome that presents with hypogonadism and is associated with metabolic syndrome. Patients demonstrating hypogonadism show a greater prevalence of metabolic syndrome due to changes in body composition. We aimed to determine the association between KS and dyslipidemia. The KS group comprised 55 patients who visited the infertility clinic for an infertility evaluation and were confirmed as having a diagnosis of KS. The control group comprised 120 patients who visited the clinic for health screening. Patient characteristics were compared between the two groups with respect to height, weight, body mass index (BMI), testosterone, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels. Height and weight were significantly greater in patients belonging to the KS group, but no statistically significant difference was found with respect to the BMI. Testosterone levels in patients belonging to the KS group were significantly lower compared to the control group (2.4 ± 2.6 vs. 5.2 ± 1.8 ng/mL, P < 0.001). Compared to the control group, TG levels in patients belonging to the KS group were increased (134.9 ± 127.8 vs. 187.9 ± 192.1 mg/dL, P = 0.004) and HDL cholesterol was significantly decreased (51.2 ± 22.0 vs. 44.0 ± 9.5 mg/dL, P = 0.009). LDL cholesterol and total cholesterol were not significantly different between the two groups (P = 0.076 and P = 0.256, respectively). Significant differences were noted between patients belonging to the KS group and normal control group with respect to elevated TG and decreased HDL cholesterol levels.

KEYWORDS:

Dyslipidemia; Hypogonadism; Klinefelter's Syndrome

PMID:
28960039
PMCID:
PMC5639067
DOI:
10.3346/jkms.2017.32.11.1848
[Indexed for MEDLINE]
Free PMC Article
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16.
Prenat Diagn. 2017 Nov;37(11):1176-1178. doi: 10.1002/pd.5153. Epub 2017 Oct 22.

Prenatal presentation of 49,XXXXY syndrome.

Author information

1
Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, MA, USA.
2
Department of Pathology, Tufts Medical Center, Boston, MA, USA.
3
Department of Pediatrics, Boston Medical Center, Boston, MA, USA.
PMID:
28940214
DOI:
10.1002/pd.5153
[Indexed for MEDLINE]
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17.
Indian J Pathol Microbiol. 2017 Jul-Sep;60(3):424-426. doi: 10.4103/IJPM.IJPM_91_16.

Incontinentia pigmenti, an x-linked dominant disorder, in a 2-year-old boy with Klinefelter syndrome.

Author information

1
Department of Dermatology, Christian Medical College, Ludhiana, Punjab, India.
2
Department of Dermatology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, Tamil Nadu, India.
3
Department of Cytogenetics, Christian Medical College, Vellore, Tamil Nadu, India.
4
Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India.
5
Department of Ophthalmology, Christian Medical College, Vellore, Tamil Nadu, India.
6
Department of Dermatology, Venereology and Leprosy, Christian Medical College, Vellore, Tamil Nadu, India.

Abstract

Incontinentia pigmenti (IP) is a rare X-linked dominant disorder, in which skin lesions distributed along Blaschko's lines appear shortly after birth. Early lesions which are erythematous/bullous evolve over time into warty lesions, hyperpigmented swirls/macules, and atrophic hypopigmented streaks. Clinical features are heterogeneous. Abnormalities of the teeth, nails, hair, eyes, central nervous system, and breast may also be present. While intelligence is generally normal, varied degrees of intellectual disability/developmental delay have been reported. Lifespan is normal. IP is associated with mutations of the inhibitor of kappa light polypeptide gene enhancer in B cell, kinase gamma (IKBKG) gene on chromosome Xq28. This gene is involved in the activation of nuclear factor kappa B which protects cells against apoptosis; therefore, cells with IKBKG mutations are extremely susceptible to apoptosis. X-linked dominant disorders are lethal to male fetuses. Males who survive with IP either have mosaicism or an additional X chromosome (Klinefelter syndrome). We present a 22-month-old boy with IP and Klinefelter syndrome.

PMID:
28937389
DOI:
10.4103/IJPM.IJPM_91_16
[Indexed for MEDLINE]
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18.
Arch Argent Pediatr. 2017 Oct 1;115(5):e282-e286. doi: 10.5546/aap.2017.e282.

[Double aneuploidy: Klinefelter and Edwards syndromes (48,XXY,+18). Case report].

[Article in Spanish; Abstract available in Spanish from the publisher]

Author information

1
Servicio de Genética, Hospital Provincial Neuquén "Dr. Eduardo Castro Rendón", provincia de Neuquén, Argentina. mailencosta89@gmail.com.
2
Servicio de Genética, Hospital Provincial Neuquén "Dr. Eduardo Castro Rendón", provincia de Neuquén, Argentina.

Abstract

The co-existence of a double chromosomal abnormality in one individual is a rare event, even more the simultaneous presence of Klinefelter (XXY) and Edwards (trisomy 18) syndrome. The aim of this article is to report the case of a newborn with a double aneuploidy, which consists in the coexistence of Edwards and Klinefelter syndrome. The patient's phenotype correlates mainly with Edwards syndrome. The diagnosis is made by performing the cytogenetics (karyotype) of peripheral blood lymphocytes. Only 15 cases of patients with Klinefelter and Edwards syndromes had been reported in literature so far.

KEYWORDS:

Double aneuploidy; Karyotype; Klinefelter Syndrome; Phenotype; Trisomy 18

PMID:
28895703
DOI:
10.5546/aap.2017.e282
[Indexed for MEDLINE]
Free full text
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19.
Science. 2017 Sep 1;357(6354):932-935. doi: 10.1126/science.aam9046. Epub 2017 Aug 17.

Fertile offspring from sterile sex chromosome trisomic mice.

Author information

1
Sex Chromosome Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
2
Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
3
Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Kyoto, 606-8501, Japan.
4
Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan. saitou@anat2.med.kyoto-u.ac.jp james.turner@crick.ac.uk.
5
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
6
Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kyoto, 606-8501, Japan.
7
Sex Chromosome Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK. saitou@anat2.med.kyoto-u.ac.jp james.turner@crick.ac.uk.

Abstract

Having the correct number of chromosomes is vital for normal development and health. Sex chromosome trisomy affects 0.1% of the human population and is associated with infertility. We show that during reprogramming to induced pluripotent stem cells (iPSCs), fibroblasts from sterile trisomic XXY and XYY mice lose the extra sex chromosome through a phenomenon we term trisomy-biased chromosome loss (TCL). Resulting euploid XY iPSCs can be differentiated into the male germ cell lineage and functional sperm that can be used in intracytoplasmic sperm injection to produce chromosomally normal, fertile offspring. Sex chromosome loss is comparatively infrequent during mouse XX and XY iPSC generation. TCL also applies to other chromosomes, generating euploid iPSCs from cells of a Down syndrome mouse model. It can also create euploid iPSCs from human trisomic patient fibroblasts. The findings have relevance to overcoming infertility and other trisomic phenotypes.

PMID:
28818972
PMCID:
PMC5581950
DOI:
10.1126/science.aam9046
[Indexed for MEDLINE]
Free PMC Article
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20.
Crim Behav Ment Health. 2018 Apr;28(2):132-140. doi: 10.1002/cbm.2052. Epub 2017 Aug 7.

Klinefelter's syndrome and sexual offending - A literature review.

Author information

1
Nottinghamshire Healthcare NHS Foundation Trust, Arnold Lodge, Cordelia Close, Leicester LE5 0LE, University of Nottingham, UK.
2
Institute of Mental Health, University of Nottingham/Nottinghamshire Healthcare NHS Foundation Trust, Rampton Hospital, Retford, Nottinghamshire, UK.

Abstract

BACKGROUND:

Klinefelter's syndrome is a sex chromosome abnormality affecting approximately 1 in 1000 men. There have been suggestions that it is associated with a higher than average prevalence of sexual offending but to what extent does research evidence support this assertion?

AIMS:

This study aimed to conduct a systematic review of published research to establish the prevalence of sexual offending in men with Klinefelter's syndrome.

METHOD:

The databases MEDLINE, PsycINFO and EMBASE were searched from inception until 31 December 2016 by using a range of terms for Klinefelter's syndrome and for sexual offending. All selected papers were examined for quality by using the Strengthening the Reporting of Observational Studies in Epidemiology checklist.

RESULTS:

We identified 53 relevant papers of which 10 met our inclusion criteria. All but one were prevalence studies conducted in a prison or hospital setting. The one, Danish, register-based cohort study did suggest an increased risk of sex offending among Klinefelter men, probably established before the diagnosis was made and, therefore, any hormone replacement instituted.

CONCLUSION:

There is insufficient evidence to date to support concerns about exceptional risk of sex offending among men with Klinefelter's syndrome. Rather, it is arguable that there is a research gap in understanding how the experience of and treatment for their condition may affect them. Copyright © 2017 John Wiley & Sons, Ltd.

PMID:
28782868
DOI:
10.1002/cbm.2052
[Indexed for MEDLINE]
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