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Concept: Klinefelter's syndrome


Context: Recently, new clinically important information regarding Klinefelter syndrome (KS) has been published. We review aspects of epidemiology, endocrinology, metabolism, body composition, and neuropsychology with reference to recent genetic discoveries. Evidence Acquisition: PubMed was searched for “Klinefelter,” “Klinefelter’s,” and “XXY” in titles and abstracts. Relevant papers were obtained and reviewed, as well as other articles selected by the authors. Evidence Synthesis: KS is the most common sex chromosome disorder in males, affecting one in 660 men. The genetic background is the extra X-chromosome, which may be inherited from either parent. Most genes from the extra X undergo inactivation, but some escape and serve as the putative genetic cause of the syndrome. KS is severely underdiagnosed or is diagnosed late in life, roughly 25% are diagnosed, and the mean age of diagnosis is in the mid-30s. KS is associated with an increased morbidity resulting in loss of approximately 2 yr in life span with an increased mortality from many different diseases. The key findings in KS are small testes, hypergonadotropic hypogonadism, and cognitive impairment. The hypogonadism may lead to changes in body composition and a risk of developing metabolic syndrome and type 2 diabetes. The cognitive impairment is mainly in the area of language processing. Boys with KS are often in need of speech therapy, and many suffer from learning disability and may benefit from special education. Medical treatment is mainly testosterone replacement therapy to alleviate acute and long-term consequences of hypogonadism as well as treating or preventing the frequent comorbidity. Conclusions: More emphasis should be placed on increasing the rate of diagnosis and generating evidence for timing and dose of testosterone replacement. Treatment of KS should be a multidisciplinary task including pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists, and endocrinologists.

Concepts: Medicine, Endocrinology, Syndromes, Klinefelter's syndrome, Aneuploidy, Y chromosome, X chromosome, Mosaic


The ratio of second to fourth digit length (2D:4D) is a correlate of prenatal testosterone. High 2D:4D is associated with low prenatal testosterone, and reduced sensitivity to testosterone. Klinefelter’s syndrome (KS; 47 XXY) affects the endocrine system, such that low testosterone levels are found in KS foetuses, new-borns and adults. To date, there are no published data regarding the pattern of 2D:4D in KS males. Here we consider 2D:4D in KS individuals (n = 51), their relatives (16 fathers and 15 mothers) and an unaffected control sample of 153 men and 153 women. Adult KS individuals were taller than their fathers and had shorter fingers than fathers and male controls. Compared with fathers, male controls and mothers, KS males had shorter fingers relative to height. With regard to 2D:4D, KS individuals had higher 2D:4D than fathers (right and left hands), male controls (right and left hands) and mothers (left hands). Among KS males older than 13 years there were 34 individuals currently prescribed testosterone and nine not prescribed. In comparison to the former, the latter individuals had higher right 2D:4D and higher right-left 2D:4D. We conclude that KS males have mean 2D:4D values similar to those found in female population norms. In addition, testosterone supplementation in KS males may be most common for individuals with low right 2D:4D.

Concepts: Gender, Testosterone, Klinefelter's syndrome, Finger, Mosaic


We present rapid aneuploidy diagnosis of de novo partial trisomy 12q (12q24.21→qter) and partial monosomy 6q (6q27→qter) by aCGH using uncultured amniocytes in a fetus with coarctation of the aorta, ventriculomegaly and thickened nuchal fold. We discuss the association of TBX3, TBX5 and MED13L gene duplication with coarctation of the aorta, and the association of RNASET2 gene haploinsufficiency with ventriculomegaly in this case.

Concepts: DNA, Chromosome, Cytogenetics, Klinefelter's syndrome, Aneuploidy, Genetic disorders, Trisomy, Karyotype


Genetic mosaicism is defined as the existence of at least two genetically distinct cell populations within one individual. Mosaic presentation of genetic disorders is common and is often particularly obvious in the skin, because there it will generate recognizable patterns. Recognizing those can frequently assist in establishing a diagnosis. In this review, we discuss the mechanisms that give rise to genetic mosaicism. We describe its most frequent cutaneous manifestations that are relevant to paediatric practice. While most mosaic genetic diseases are rare, it is important to recognize them so that patients and parents may receive appropriate genetic counselling. Moreover, recent developments are now resulting in novel, targeted treatments for such disorders that promise to considerably improve patients' lives.

Concepts: Genetics, Disease, Genetic disorder, Mutation, Skin, Klinefelter's syndrome, Medical genetics, Chimera


OBJECTIVE: The objective of the study was to evaluate the ability of a new prenatal diagnostic platform - prenatal BACs-on-Beads™ (BoBs™) in detecting mosaicism by comparison to quantitative fluorescence-polymerase chain reaction (QF-PCR). METHODS: A validation study of prenatal BoBs™ was firstly performed using 18 artificially constructing mosaic samples involving various aneuploidies and microdeletion conditions. Additionally, we compared the accuracy between prenatal BoBs™ and QF-PCR for 18 archived clinical mosaic cases and nine chromosomally abnormal cell lines with reference to conventional karyotype results. RESULTS: In the validation study, BoBs™ allowed the detection of mosaicism at a level of 20-40%. Among the clinical mosaic cases, 14/18 cases were within the detection of BoBs™, 8/14 (57.1%) could be identified by BoBs™ and 6/9 (66.7%) by QF-PCR, but 6/14 (42.9%) were missed by both tests. Three cases (16.7%) were detected by prenatal BoBs™ but missed by QF-PCR, whereas QF-PCR detected one case that was missed by BoBs™. The overall sensitivity of BoBs™ in detecting mosaicism is 44.4% (8/18), which is slightly higher than that of QF-PCR (33.3%; 6/18). CONCLUSION: Prenatal BoBs™ has a sensitivity of 57.1% in the detection clinical mosaic cases. According to the validation test, mosaicism of 20% or greater is detectable by the BoBs™ assay. © 2012 John Wiley & Sons, Ltd.

Concepts: Detection theory, Klinefelter's syndrome, John Wiley & Sons


Pallister-Killian syndrome is a rare, multi-system developmental diagnosis typically caused by tetrasomy of chromosome 12p that exhibits tissue-limited mosaicism. The spectrum of clinical manifestations in Pallister-Killian syndrome is wide and includes craniofacial anomalies, clefts, ophthalmologic, audiologic, cardiac, musculoskeletal, diaphragmatic, gastrointestinal, genitourinary, and cutaneous anomalies in association with intellectual disability and seizures. Growth parameters are often normal to elevated at birth with deceleration of growth postnatally. No formal estimate of the prevalence of Pallister-Killian syndrome has been made. Here, we report the clinical findings in 59 individuals with Pallister-Killian syndrome who were ascertained at Pallister-Killian syndrome Foundation family meetings held in the summers of 2006, 2008, 2009, and 2010. In addition, the clinical findings of 152 cases reported in the medical literature were reviewed and compared to the cohort examined here. Several novel clinical characteristics were identified through detailed dysmorphology examinations of this cohort and reassertion of a mild developmental variant is described. This report expands the clinical manifestations of Pallister-Killian syndrome and highlights the variable expressivity of this diagnosis with important implications for diagnosis and counseling. © 2012 Wiley Periodicals, Inc.

Concepts: Medicine, The Canon of Medicine, Avicenna, Report, Syndromes, Down syndrome, Expressivity, Klinefelter's syndrome


Uniparental disomy (UPD) is an uncommon chromosome condition, but UPD involving chromosome 21 is rarely reported. We reported here a case who had first trimester screening test for Down syndrome, chorionic villus sampling for fetal karyotyping, quantitative fluorescence polymerase chain reaction (QF-PCR), as well as non-invasive prenatal testing (NIPT) by maternal plasma sequencing. There were discordant results between fetal karyotyping and NIPT due to UPD 21combined with confined placental mosaicism of trisomy 21. This demonstrated that it is possible to detect placental mosaicism by NIPT, but further studies are required to confirm its sensitivity. Therefore, all positive NIPT results must be confirmed by conventional invasive test and karyotyping. QF-PCR has the additional benefit in diagnosing UPD. © 2013 John Wiley & Sons, Ltd.

Concepts: Pregnancy, Cytogenetics, Chromosomal translocation, Down syndrome, Klinefelter's syndrome, Aneuploidy, Trisomy, Karyotype


49, XXXXY is a rare aneuploidy and variant of Klinefelter syndrome, occurring in 1 per 80,000-100,000 live births. We present a cohort of 40 affected males, focusing on musculoskeletal problems. Subjects were participants in an annual 49er family support group meeting. Children were examined in a multidisciplinary clinic by a pediatric neurologist and geneticist, a pediatric orthopedist, a neurodevelopmentalist, and two physical therapists. The patient data were collected from this clinic from 2004 to 2012. All patients were required to have karyotypes that confirmed the presence of XXXXY. There was a high prevalence of musculoskeletal disorders, particularly hypotonia (34 patients [85%]), radioulnar synostosis (30 [75%]), pes planus (26 [65%]), asymmetric hip rotation (27 [67.5%]), and clinodactyly (24 [60%]). Other, less common lower-extremity disorders, included, 5 patients (12.5%) with unilateral club foot, 5 boys (12.5%) with pes cavus, 10 patients (25%) genu valgum and 2 children with genu varus (5%). To our knowledge, this is the first large cohort of boys with 49, XXXXY that focuses on musculoskeletal disorders. There was an increased incidence of hypotonia, clubfoot, avascular necrosis of the femoral head, radioulnar synostosis, and pes planus compared to the normative population. Boys with 49, XXXXY would benefit from multidisciplinary evaluations, particularly from pediatric orthopedists, physical therapists, neurologists, and geneticists for appropriate medical care. © 2013 Wiley Periodicals, Inc.

Concepts: Varus deformity, Neurology, Avascular necrosis, Klinefelter's syndrome, Aneuploidy, Genu valgum, Genu varum, Congenital disorders of musculoskeletal system


47,XXY (Klinefelter syndrome) is the most frequent sex chromosomal disorder and affects approximately one in 660 newborn boys. The syndrome is characterized by varying degrees of cognitive, social, behavioral, and learning difficulties and in adulthood additionally primary testicular failure with small testes, hypergonadotropic hypogonadism, tall stature, and eunuchoid body proportions. The phenotype is variable ranging from “near-normal” to a significantly affected individual. In addition, newborns with Klinefelter syndrome generally present with a normal male phenotype and the only consistent clinical finding in KS is small testes, that are most often not identified until after puberty. Decreased awareness of this syndrome among health professionals and a general perception that all patients with 47,XXY exhibit the classic textbook phenotype results in a highly under-diagnosed condition with up to 75% of the patients left undetected. Typically, diagnosis is delayed with the majority of patients identified during fertility workup in adulthood, and only 10% of patients diagnosed prior to puberty. Early detection of this syndrome is recommended in order to offer treatment and intervention at the appropriate ages and stages of development for the purpose of preventing osteopenia/osteoporosis, metabolic syndrome, and other medical conditions related to hypogonadism and to the XXY as well as minimizing potential learning and psychosocial problems. The aim of this review is to present the clinical aspects of XXY and the age-specific recommendations for medical management. © 2013 Wiley Periodicals, Inc.

Concepts: Psychology, Syndromes, Testicle, Klinefelter's syndrome, Aneuploidy, Y chromosome, Puberty, X chromosome


X and Y chromosomal variations including tetrasomy and pentasomy conditions are rare and occur in 1:18,000-1:100,000 male births. The most common sex chromosome aneuploidy is 47, XXY for which there is a rich literature delineating the physical and neurobehavioral phenotype. Although the more complex chromosome aneuploidies 48, XXYY, 48, XXXY, and 49, XXXXY are often compared with 47, XXY (Klinefelter syndrome) because of shared features including tall stature and hypergonadotropic hypogonadism, there is a wider spectrum of physical and cognitive abilities that have recently been delineated. The phenotypic presentation of the boys with more severe aneuploidy shares some characteristics with 47, XXY, but there are also other unique and distinctive features. Previously unappreciated intact nonverbal skills have been demonstrated in association with severe developmental dyspraxia. MRI findings of white matter hyperintensities may underlie cognitive deficits and deserve further study. This report discusses what is known about clinical variability in the XY syndromes collectively evaluated through careful multidisciplinary clinical evaluation including the clinical and neurobehavioral aspects of these conditions. Variability in clinical and cognitive functioning may reflect skewed X inactivation, mosaicism, or epigenetic factors that warrant further investigation. © 2013 Wiley Periodicals, Inc.

Concepts: Chromosome, Klinefelter's syndrome, Aneuploidy, Y chromosome, X chromosome, X-inactivation, Mosaic, Tetrasomy