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Systemic lupus erythematosus (SLE) disproportionately affects females. Recent work demonstrates that men with Klinefelter's syndrome (47,XXY males) have a similar risk of developing SLE as do genotypic females. We present an unusual case of an African American family with two SLE affected individuals in which one of the SLE patients also has Turner's syndrome [46,X,del(X)(q13)]. While not definitive, this family raises interesting questions regarding the role of genes located on the X chromosome in the development of SLE. The paucity of case reports documenting the overlap of SLE with Turner's syndrome while there is and association of male SLE with Klinefelter's syndrome suggests a lower risk of SLE in Turner's females. These observations are consistent with a gene dose effect at X with two X chromosomes (46,XX or 47,XXY) conferring higher risk and one X chromosome (46,XY or 45,XO) conferring lower risk of SLE.

Similar to other autoimmune diseases, systemic lupus erythematosus (SLE) predominately affects women. Recent reports demonstrate excess Klinefelter’s among men with SLE and a possible under-representation of Turner’s syndrome among women with SLE as well as a case report of a 46,XX boy with SLE. These data suggest that risk of SLE is related to a gene dose effect for the X chromosome. Such an effect could be mediated by abnormal inactivation of genes on the X chromosome as has been demonstrated for CD40L, or by genetic polymorphism as has been demonstrated for Xq28. On the other hand, a gene dose effect could also be mediated by a gene without an SLE-associated polymorphism in that a gene that avoids X inactivation will have a higher level of expression in persons with two X chromosomes.

Systemic lupus erythematosus (SLE) is more common among women than men with a ratio of about 10 to 1. We undertook this study to describe familial male SLE within a large cohort of familial SLE. SLE families (two or more patients) were obtained from the Lupus Multiplex Registry and Repository. Genomic DNA and blood samples were obtained using standard methods. Autoantibodies were determined by multiple methods. Medical records were abstracted for SLE clinical data. Fluorescent in situ hybridization (FISH) was performed with X and Y centromere specific probes, and a probe specific for the toll-like receptor 7 gene on the X chromosome. Among 523 SLE families, we found five families in which all the SLE patients were male. FISH found no yaa gene equivalent in these families. SLE-unaffected primary female relatives from the five families with only-male SLE patients had a statistically increased rate of positive ANA compared to SLE-unaffected female relatives in other families. White men with SLE were 5 times more likely to have an offspring with SLE than were White women with SLE but there was no difference in this likelihood among Black men. These data suggest genetic susceptibility factors that act only in men.

Background

The association of achondroplasia and Klinefelter syndrome is extremely rare. To date, five cases have been previously reported, all of them diagnosed beyond the postnatal period, and only one was molecularly characterized. We describe the first case of this unusual association diagnosed in the neonatal period, the clinical findings and the molecular studies undertaken.

Case presentation

The boy was born at term with clinical and radiological features indicating the diagnosis of achondroplasia or hypochondroplasia combined with the prenatal karyotype of Klinefelter syndrome (47,XXY). Neonatal FGFR3 mutation screening showed that the newborn was heterozygous for the classic achondroplasia G340R mutation. Microsatellite marker analysis showed that the sex chromosome aneuploidy had arisen from a non-disjunction error in paternal meiosis I, with a recombination event in the pseudoautosomal region 1 (PAR1).

Conclusion

Specific mutation analysis is appropriate to confirm the clinical diagnosis of achondroplasia for appropriate diagnosis, prognosis, and genetic counseling, especially when the karyotype does not explain the abnormal prenatal sonographic findings. In the present case, a recombination event was observed in the PAR1 region, although recombinational events in paternally derived Klinefelter syndrome cases are much rarer than expected.

Klinefelter's syndrome is a sex chromosome abnormality with low androgen level. The varied manifestations of the mental symptoms in some of them, that are inexplicable based on their genotype alone, has fascinated the researchers. We present here a case of Klinefelter's syndrome having a karyotype of mos 47, XXY, and also inversion in 9th chromosome, with schizophrenia. Despite the view that inv 9 is a normal variant, it is still worthwhile to explore whether it has any role in the etiology of schizophrenia especially when it occurs with other genotypic aberrations that are suspected to have relevance to psychiatric disorders including the Klinefelter's syndrome.

Klinefelter syndrome is the most common chromosomal aneuploidy in men (XXY karyotype, 1 in 600 live births) and results in testicular (infertility and androgen deficiency) and nontesticular (cognitive impairment and osteoporosis) deficits. The extent to which skeletal changes are due to testosterone deficiency or arise directly from gene overdosage cannot be determined easily in humans. To answer this, we generated XXY mice through a four-generation breeding scheme. Eight intact XXY and 9 XY littermate controls and 8 castrated XXY mice and 8 castrated XY littermate controls were euthanized at 1 year of age. Castration occurred 6 months prior to killing. A third group of 9 XXY and 11 XY littermates were castrated and simultaneously implanted with a 1-cm Silastic testosterone capsule 8 weeks prior to sacrifice. Tibias were harvested from all three groups and examined by micro–computed tomography and histomorphometry. Blood testosterone concentration was assayed by radioimmunoassay. Compared with intact XY controls, intact androgen-deficient XXY mice had lower bone volume (6.8% ± 1.2% versus8.8% ± 1.7%, mean ± SD, p = .01) and thinner trabeculae (50 ± 4 µm versus 57 ± 5 µm, p = .007). Trabecular separation (270 ± 20 µm versus 270 ± 20 µm) or osteoclast number relative to bone surface (2.4 ± 1.0/mm2 versus 2.7 ± 1.5/mm2) did not differ significantly. Testosterone-replaced XXY mice continued to show lower bone volume (5.5% ± 2.4% versus 8.1% ± 3.5%, p = .026). They also exhibited greater trabecular separation (380 ± 69 µm versus 324 ± 62 µm, p = .040) but equivalent blood testosterone concentrations (6.3 ± 1.8 ng/mL versus 8.2 ± 4.2 ng/mL, p = .28) compared with testosterone-replaced XY littermates. In contrast, castration alone drastically decreased bone volume (p < .001), trabecular thickness (p = .05), and trabecular separation (p < .01) to such a great extent that differences between XXY and XY mice were undetectable. In conclusion, XXY mice replicate many features of human Klinefelter syndrome and therefore are a useful model for studying bone. Testosterone deficiency does not explain the bone phenotype because testosterone-replaced XXY mice show reduced bone volume despite similar blood testosterone levels. © 2010 American Society for Bone and Mineral Research.

A 39 year old male with primary infertility was diagnosed as having Klinefelter syndrome by conventional cytogenetic analysis, which also showed an abnormal chromosome 12. Fluorescence in situ hybridisation (FISH) analysis of the aberrant chromosome using a 12 specific centromeric probe showed a break in the alphoid repeats followed by an inversion within the short arm, resulting in a pseudodicentric chromosome. Further FISH analyses using telomeric and subtelomeric probes showed that the other breakpoint was in the subtelomeric region of the short arm. The karyotype is designated 47,XXY,inv(12)(p10p13.3). To our knowledge this is the first report of a case of "centric inversion".

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Two cases of benign neurogenic amyotrophy associated with Klinefelter's syndrome are reported. Both presented with slowly progressive, diffuse neurogenic muscle atrophy of juvenile onset. Both had a karyotype of XXY. Amplification, by the polymerase chain reaction, of a fragment of androgen receptor that was related to bulbospinal muscular atrophy, showed no abnormality. Treatment with androgen in one case provided no benefit. Benign neurogenic amyotrophy in the Klinefelter's syndrome is likely to be an independent type of motor neuron disease and suggests that the X chromosome plays an important part in the biology of motor neurons.

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A very rare case of complete testicular feminisation with a 47,XXY sex chromosome complement is described. The X-chromatin is positive. The subject studied, who belongs to a family in which four other members have Morris's syndrome and have a 46,XY karyotype, is a perfect phenotypic female. The endocrine situation is unique and resembles, in part, that of subjects with Klinefelter's syndrome.

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Background

Autoimmune thyroid disease is common in systemic lupus erythematosus (SLE). About 20% of patients with SLE have secondary Sjögren's syndrome.

Methods

Families with more than one patient with SLE were identified. All patients met the revised classification criteria, although SLE‐unaffected relatives were confirmed not to satisfy these criteria. Diagnosis of autoimmune thyroid disease and Sjögren's syndrome was made on the basis of a review of medical records, interview and questionnaire administered to patients with SLE, and by a questionnaire administered to SLE‐unaffected subjects.

Results

Of a total of 1138 patients with SLE, 169 had a diagnosis of Sjögren's syndrome. Of these 50 (29.6%) patients also had autoimmune thyroid disease. Of the 939 patients with SLE with no diagnosis of Sjögren's syndrome, 119 (12.7%) had autoimmune thyroid disease (χ2 = 20.1, p = 0.000009). There was no association of a diagnosis of hypertension with secondary Sjögren's syndrome (42% vss 47%). Among 2291 SLE‐unaffected relatives, 44 had diagnosed primary Sjögren's syndrome and 16 (36.3%) of these also had autoimmune thyroid disease. 265 of 2247 (11.8%) subjects had autoimmune thyroid disease but no Sjögren's syndrome (χ2 = 24.2, p<0.001).

Conclusions

Autoimmune thyroid disease is found in excess among patients with SLE with a diagnosis of secondary Sjögren's syndrome, as well as among their SLE‐unaffected relatives with a diagnosis of primary Sjögren's syndrome.

Purpose

Sex chromosome trisomies (SCTs) are found on amniocentesis in 2.3–3.7 per 1000 same-sex births, yet there is a limited database on which to base a prognosis. Autism has been described in postnatally diagnosed cases of Klinefelter syndrome (XXY karyotype), but the prevalence in non-referred samples, and in other trisomies, is unclear. The authors recruited the largest sample including all three SCTs to be reported to date, including children identified on prenatal screening, to clarify this issue.

Design

Parents of children with a SCT were recruited either via prenatal screening or via a parental support group, to give a sample of 58 XXX, 19 XXY and 58 XYY cases. Parents were interviewed using the Vineland Adaptive Behavior Scales and completed questionnaires about the communicative development of children with SCTs and their siblings (42 brothers and 26 sisters).

Results

Rates of language and communication problems were high in all three trisomies. Diagnoses of autism spectrum disorder (ASD) were found in 2/19 cases of XXY (11%) and 11/58 XYY (19%). After excluding those with an ASD diagnosis, communicative profiles indicative of mild autistic features were common, although there was wide individual variation.

Conclusions

Autistic features have not previously been remarked upon in studies of non-referred samples with SCTs, yet the rate is substantially above population levels in this sample, even when attention is restricted to early-identified cases. The authors hypothesise that X-linked and Y-linked neuroligins may play a significant role in the aetiology of communication impairments and ASD.

The most common sex chromosome complex in sex chromatin-positive males with Klinefelter's syndrome is XXY. When the complex is XXYY or XXXY, the clinical findings do not seem to differ materially from those seen in XXY subjects, although more patients with these intersexual chromosome complements need to be studied to establish possible phenotypical expressions of the chromosomal variants.

Two male children with an XXXXY sex chromosome abnormality are described. The data obtained from the study of these cases and five others described in the literature suggest that the XXXXY patient is likely to have congenital defects not usually seen in the common form of the Klinefelter syndrome. These include a triad of (1) skeletal anomalies (including radioulnar synostosis), (2) hypogenitalism (hypoplasia of penis and scrotum, incomplete descent of testes and defective prepubertal development of seminiferous tubules), and (3) greater risk of severe mental deficiency.

That the conclusions are based on data from a small number of patients is emphasized, together with the need for a cytogenetic survey of a large control or unselected population.

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Hypostatic leg ulcers, probably secondary to vascular insufficiency, were observed in two adult men with 47,XXY Klinefelter's syndrome. The association between leg ulcers and 47,XXY Klinefelter's syndrome deserves increased attention because knowledge of the association may alert clinicians to an otherwise unsuspected chromosome abnormality.

Kennedy's disease, an X-linked spinal and bulbar muscular atrophy, is characterized by loss of lower motor neurons. Mild sensory deficits, gynecomastia and infertility may be observed. Klinefelter's syndrome is a variation of sex chromosome disorder characterized by hypogonadism, gynecomastia and azoospermia, and the most frequent karyotype is XXY. A 55-year-old man who presented with slowly progressive and diffuse neurogenic muscle atrophy without bulbar or sensory symptoms. He also had Klinefelter's syndrome. Genetic study of Kennedy's disease was normal. Our patient differs from those with Kennedy's disease in the absence of bulbar and sensory symptoms. It is suggested that the X chromosome plays an important role in the biology of motor neurons.

Klinefelter's syndrome is characterized by abnormal karyotype 47, XXY and a phenotype associated with hypogonadism and gynecomastia. Often the disease can be diagnosed accidentally, when carrying out cytogenetic analysis in cases of a malignant blood disease. We present the clinical case of a patient diagnosed with acute myelomonoblastic leukemia-M4 Eo (AML- M4), where by means of classic cytogenetics a karyotype was found corresponding to Klinefelter's syndrome. Three induction courses of polychemotherapy wermade, which led to remission of the disease, documented both flowcytometrically and cytogenetically.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving critical genetic and environmental risk factors. SLE is a relatively common disease among African American women, affecting as many as one in 250. A collection of more than 250 African American and European American pedigrees multiplex for SLE have been collected in Oklahoma over the past decade for the purpose of identifying the genetic risk factors involved in the pathogenesis of SLE. A genome scan has been performed, and interestingly, the linkage results usually dominate in families from one or the other of these ethnicities. For example, the linkage effect at 1q21-22 near FcgammaRIIA is much stronger in the African American pedigrees than in the European American pedigrees. On the other hand, a gene near the top of chromosome4 (at 4p l6-15) contributes to SLE in the European American pedigrees, but not in the African American pedigrees. The racially-specific results lead to the tentative conclusion of genetic differences associated with SLE in African Americans and European Americans. The identification of the genes responsible for the observed linkage effects will provide fundamental knowledge concerning SLE and may even provide new targets for therapy and strategies to defeat this enigmatic and difficult disease.

A 16 years old boy with Chronic Renal Failure (CRF) was not suspected of having Klinefelter’s syndrome until he complained of painful gynecomastia. He was under haemodialysis for 2 years. At first, he was in an approximately full pubertal development (P5, G5), but he had a small and a firm testis (length 2.2cm) and some degree of facial male pattern hair. He also had a decreased upper to lower body segment ratio and despite having chronic renal failure, he was taller than his parents and siblings. His laboratory tests showed high levels of FSH and normal levels of LH and testosterone. With regards to all these findings, we suspected that there might be an occult Klinefelter’s syndrome. So, we made his karyotype that showed a 47XXY pattern. Because there are only a few number of cases that have occult Klinefelter’s syndrome in the basis of chronic renal failure, we decided to report this case.

Our goal in the present work was to determine whether male patients with untreated hypogonadism have an increased risk of developing rheumatic/autoimmune disease (RAD), and, if so, whether there is a relation to the type of hypogonadism. We carried out neuroendocrine, genetic, and rheumatologic investigations in 13 such patients and 10 healthy male 46,XY normogonadic control subjects. Age and body mass index were similar in the two groups. Nine of the 13 patients had hypergonadotropic hypogonadism (five of whom had Klinefelter's syndrome [karyotype 47,XXY]) and 4 of the 13 had hypogonadotropic hypogonadism (46,XY). Of these last four, two had Kallmann's syndrome and two had idiopathic cryptorchidism.

Eight (61%) of the 13 patients studied had RADs unrelated to the etiology of their hypogonadism. Of these, four had ankylosing spondylitis and histocompatibility B27 antigen, two had systemic lupus erythematosus (in one case associated with antiphospholipids), one had juvenile rheumatoid arthritis, and one had juvenile dermatomyositis. In comparison with the low frequencies of RADs in the general population (about 0.83%, including systemic lupus erythematosus, 0.03%; dermatomyositis, 0.04%; juvenile rheumatoid arthritis, 0.03%; ankylosing spondylitis, 0.01%; rheumatoid arthritis, 0.62%; and other RAD, 0.1%), there were surprisingly high frequencies of such disorders in this small group of patients with untreated hypogonadism (P < 0.001) and very low serum testosterone levels (P = 0.0005). The presence of RADs in these patients was independent of the etiology of their hypogonadism and was associated with marked gonadal failure with very low testosterone levels.

A case of Klinefelter's syndrome presenting with systemic lupus erythematosus while receiving androgen replacement therapy is described. The association of systemic lupus erythematosus with Klinefelter's syndrome is discussed, particularly in terms of the effect of sex hormones.

We describe a man with Becker muscular dystrophy whose weakness was minimal in contrast to that of his more severely affected nephews. This man had a Klinefelter karyotype (47,XXY) and his mild symptoms may be attributed to him being heterozygous for the muscular dystrophy gene. This is the first report of a person with both Klinefelter's syndrome and Becker muscular dystrophy. This combination may be one explanation for the variable expression of X linked muscular dystrophy noted in some pedigrees.

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A 14-month-old boy with double aneuploidy and a double aortic arch suffered from frequently recurrent severe feeding and respiratory problems. Chromosomal analysis showed a 48,XXY + 21 karyotype: a double aneuploidy of Down syndrome (DS) and Klinefelter syndrome (KS). Only four cases of double aneuploidy (DS + KS) associated with congenital heart defects have been published of which none had a double aortic arch. Our case report should draw attention to the possibility of a double aortic arch in patients with severe feeding and respiratory problems and a double aneuploidy.

Over 100 cases of 49,XXXXY syndrome have been published to date. Classic findings include radioulnar synostosis, hypogonadism, and mental retardation. The majority of reported cases have not distinguished the 49,XXXXY syndrome from Klinefelter syndrome (47,XXY), and these patients are frequently labelled as having Klinefelter syndrome or as being a "Klinefelter variant." Because of distinct clinical features, we delineate the 49,XXXXY syndrome as separate from Klinefelter syndrome, and emphasise the prevalence of congenital heart defects. We also report three new cases of 49,XXXXY syndrome and briefly discuss patient management.

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We report a case of a patient who presented with anterior mediastinal mass, seizure disorder, and mental retardation. Computerized tomography–guided fine-needle aspiration biopsy of the mass showed nonseminomatous germ cell tumor. Chromosomal analysis showed XXY karyotype. A diagnosis of Klinefelter syndrome and mediastinal germ cell tumor was made.

Purpose

The causes of male infertility are heterogeneous but more than 50% of cases have a genetic basis. Specific genetic defects have been identified in less than 20% of infertile males and, thus, most causes remain to be elucidated. The most common cytogenetic defects associated with nonobstructive azoospermia are numerical and structural chromosome abnormalities, including Klinefelter syndrome (47,XXY) and Y chromosome microdeletions. To refine the incidence and nature of chromosomal aberrations in males with infertility we reviewed cytogenetic results in 668 infertile men with oligozoospermia and azoospermia.

Materials and Methods

High resolution Giemsa banding chromosome analysis and/or fluorescence in situ hybridization were done in 668 infertile males referred for routine cytogenetic analysis between January 2004 and March 2009.

Results

The overall incidence of chromosomal abnormalities was about 8.2%. Of the 55 patients with abnormal cytogenetic findings sex chromosome aneuploidies were observed in 29 (53%), including Klinefelter syndrome in 27 (49%). Structural chromosome abnormalities involving autosomes (29%) and sex chromosomes (18%) were detected in 26 infertile men. Abnormal cytogenetic findings were observed in 35 of 264 patients (13.3%) with azoospermia and 19 of 365 (5.2%) with oligozoospermia.

Conclusions

Structural chromosomal defects and low level sex chromosome mosaicism are common in oligozoospermia cases. Extensive cytogenetic assessment and fluorescence in situ hybridization may improve the detection rate in males with oligozoospermia. These findings highlight the need for efficient genetic testing in infertile men so that couples may make informed decisions on assisted reproductive technologies to achieve parenthood.

The pathogenesis of systemic lupus erythematosus (SLE) is multifactorial and multigenetic. The apoptosis genes, fas and fas ligand (fasL), are candidate contributory genes in human SLE, as mutations of these genes result in autoimmunity in several murine models of this disease. In humans, fas mutations result in a familial autoimmune lymphoproliferative syndrome, but defects in FasL have not yet been identified. In this study, DNA from 75 patients with SLE was screened by single-stranded conformational polymorphism analysis for potential mutations of the extracellular domain of FasL. A heterozygous single-stranded conformational polymorphism for FasL, was identified in one SLE patient, who exhibited lymphadenopathy. Molecular cloning and sequencing indicated that the genomic DNA of this patient contained an 84-bp deletion within exon 4 of the fasL gene, resulting in a predicted 28 amino acid in-frame deletion. Analysis of PBMC from this patient revealed decreased FasL activity, decreased activation-induced cell death, and increased T cell proliferation after activation. This is the first report of defective FasL-mediated apoptosis related to a mutation of the human Fasl, gene in a patient with SLE and suggests that fasL mutations are an uncommon cause of the disease.