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1.
Rev Med Chil ; 147(4): 518-521, 2019 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-31344216

RESUMO

Klinefelter syndrome (47, XXY in most cases) is a frequently underdiagnosed chromosomal anomaly associated with multiple comorbidities in adult life. Patients with Klinefelter syndrome have a higher risk of cancer. Specifically, these patients have a higher risk for mediastinal germ cell tumors. It is estimated that 8% of male patients with mediastinal tumors have Klinefelter. We report a 42-years-old male who suffered recurrent respiratory infections. During the study, a mediastinal mass was found, whose pathological study disclosed a type B thymoma. The patient had a history of infertility, high stature, gynecomastia, obesity with gynecoid distribution of body fat and testicular atrophy. A karyotype was requested (47, XXY), confirming the diagnosis of Klinefelter syndrome.


Assuntos
Síndrome de Klinefelter/patologia , Timoma/patologia , Neoplasias do Timo/patologia , Adulto , Humanos , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/genética , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/patologia , Radiografia Torácica , Timoma/diagnóstico por imagem , Neoplasias do Timo/diagnóstico , Tomografia Computadorizada por Raios X
3.
Congenit Anom (Kyoto) ; 59(2): 43-46, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29732662

Assuntos
Aneuploidia , Síndrome de Klinefelter/mortalidade , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/mortalidade , Transtornos dos Cromossomos Sexuais/mortalidade , Síndrome da Trissomía do Cromossomo 18/mortalidade , Cariótipo XYY/mortalidade , Cromossomos Humanos X/química , Cromossomos Humanos X/genética , Cromossomos Humanos Y/química , Permeabilidade do Canal Arterial/genética , Permeabilidade do Canal Arterial/mortalidade , Permeabilidade do Canal Arterial/patologia , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/mortalidade , Cardiopatias Congênitas/patologia , Comunicação Interatrial/genética , Comunicação Interatrial/mortalidade , Comunicação Interatrial/patologia , Comunicação Interventricular/genética , Comunicação Interventricular/mortalidade , Comunicação Interventricular/patologia , Humanos , Lactente , Recém-Nascido , Cariótipo , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Masculino , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/genética , Transtornos dos Cromossomos Sexuais/patologia , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/patologia , Análise de Sobrevida , Trissomia/genética , Trissomia/patologia , Síndrome da Trissomía do Cromossomo 18/genética , Síndrome da Trissomía do Cromossomo 18/patologia , Cariótipo XYY/genética , Cariótipo XYY/patologia
4.
J Endocrinol Invest ; 42(7): 833-842, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30499012

RESUMO

PURPOSE: The aim of this study was to study the incidence of Y chromosome microdeletions in a Caucasian population of Klinefelter syndrome (KS) patients and to investigate the possible association between Y chromosome microdeletions and KS. MATERIALS AND METHODS: We conducted a retrospective study on 118 KS patients, 429 patients with non-obstructive azoospermia (NOA), and 155 normozoospermic men. Eight of the 118 KS patients had undergone testicular sperm extraction (TESE). All patients underwent semen examination and Y chromosome microdeletions evaluated by PCR, using specific sequence tagged site (STS) primer sets, which spanned the azoospermia factor AZFa, AZFb, and AZFc regions of the Y chromosome. RESULTS: Semen analysis of the KS group revealed: 1 patient with oligozoospermia, 1 with severe oligoasthenoteratozoospermia, 2 with cryptozoospermia, and 114 with azoospermia. Eight of the 114 azoospermic KS patients underwent TESE, and spermatozoa were recovered from three of these, all of whom had non-mosaic karyotype 47, XXY. 10.7% of the NOA patients presented AZF microdeletions. In 429 cases with NOA, 8 cases had AZFa + b + c deletion, 6 cases had AZF b + c deletion, 4 cases had AZFa microdeletion, 8 cases had AZFb microdeletion, and 20 cases had AZFc microdeletion. Just one KS patient (0.8%) presented microdeletion in the AZFc region. CONCLUSION: The percentage of microdeletions in KS patients was lower than in NOA patients, suggesting that AZF microdeletions and KS do not have a causal relationship and that Y chromosome microdeletions are not a genetic factor linked to KS.


Assuntos
Biomarcadores/análise , Deleção Cromossômica , Cromossomos Humanos Y/genética , Síndrome de Klinefelter/epidemiologia , Síndrome de Klinefelter/genética , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Incidência , Itália/epidemiologia , Síndrome de Klinefelter/patologia , Masculino , Prognóstico , Estudos Retrospectivos
5.
Eur J Med Genet ; 62(3): 210-216, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30031153

RESUMO

49,XXXXY syndrome is a rare sex chromosome aneuploidy syndrome. Cognitive impairment with expressive language deficits in combination with developmental and speech dyspraxia are cardinal symptoms. Testicular insufficiency becomes apparent during adolescence. Neurological, musculoskeletal, genital, orthodontic and immunological anomalies are common and a higher incidence of congenital malformations has been described. Here we show the evolving clinical and facial phenotype of eight boys and men with 49,XXXXY, demonstrating an increasingly perceptible distinct facial gestalt over time. In addition, almost all patients had muscular hypotonia, radioulnar synostosis, white matter anomalies, fifth-finger clinodactyly, recurrent respiratory infections in early childhood and teeth anomalies. IQ scores ranged between 40 and 70. Though many boys showed short stature at some point in early childhood, most outgrew it. As more long term data of boys and men with 49,XXXXY become available, parents of affected boys can be counseled more specifically as to the expected course and spectrum of this rare chromosomal disorder. Moreover, the multidisciplinary support can be optimized und unnecessary diagnostics avoided.


Assuntos
Síndrome de Klinefelter/patologia , Fenótipo , Adolescente , Criança , Pré-Escolar , Humanos , Masculino , Adulto Jovem
6.
World J Surg Oncol ; 16(1): 227, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30453967

RESUMO

BACKGROUND: Calcifying nested stromal epithelial tumor (CNSET) is a primary neoplasm of the liver, characterized by well-demarcated nests consisting of spindle and epithelioid cells with calcification and bone formation. An association of Cushing syndrome with CNSET has drawn attention, but the origin of CNSET has not been clarified. CASE PRESENTATION: We report here the case of a 20-year-old male with Klinefelter syndrome who underwent liver resection for an increasing liver tumor that was pathologically diagnosed with CNSET. He was postoperatively followed up and received several examinations, and recurrences and extrahepatic lymph node metastases were detected on the 64th day after surgery. Chemoembolization and chemotherapy were not effective, leading to tumor progression with development of progressive liver failure, and the patient finally died 164 days after hepatectomy. CONCLUSIONS: This case suggests that an imbalance of hormones affects the genesis and progression of CNSET, and indicates the importance of closely following patients with CNSET by imaging with attention to hepatic recurrence and extrahepatic metastases.


Assuntos
Calcinose/patologia , Células Epiteliais/patologia , Síndrome de Klinefelter/patologia , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Complexas Mistas/patologia , Células Estromais/patologia , Adulto , Calcinose/complicações , Calcinose/terapia , Terapia Combinada , Embolização Terapêutica , Evolução Fatal , Hepatectomia , Humanos , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/terapia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/terapia , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/complicações , Recidiva Local de Neoplasia/terapia , Neoplasias Complexas Mistas/complicações , Neoplasias Complexas Mistas/terapia , Adulto Jovem
7.
Sci Rep ; 8(1): 13740, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30213969

RESUMO

Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000 newborn boys making it the most frequent sex chromosome aneuploidy in the general population. The molecular basis for the phenotypic traits and morbidity in KS are not clarified. We performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes, which may be involved in X chromosome inactivation in KS.


Assuntos
Metilação de DNA/genética , Síndrome de Klinefelter/genética , Inativação do Cromossomo X/genética , Adulto , Cromossomos Humanos X/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Recém-Nascido , Síndrome de Klinefelter/patologia , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Transcriptoma/genética
8.
Epilepsy Res ; 145: 89-92, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29933145

RESUMO

Heterozygous de novo or inherited pathogenic variants in the PCDH19 gene cause a spectrum of neurodevelopmental features including developmental delay and seizures. PCDH19 epilepsy was previously known as "epilepsy and mental retardation limited to females", since the condition almost exclusively affects females. It is hypothesized that the co-existence of two populations of neurons, some with and some without PCDH19 protein expression, results in pathologically abnormal interactions between these neurons, a mechanism also referred to as cellular interference. Consequently, PCDH19-related epilepsies are inherited in an atypical X-linked pattern, such that hemizygous, non-mosaic, 46,XY males are typically unaffected, while individuals with a disease-causing PCDH19 variant, mainly heterozygous females and mosaic males, are affected. As a corollary to this hypothesis, an individual with Klinefelter syndrome (KS) (47,XXY) who has a heterozygous disease-causing PCDH19 variant should develop PCDH19-related epilepsy. Here, we report such evidence: - a male child with KS and PCDH19-related epilepsy - supporting the PCDH19 cellular interference disease hypothesis.


Assuntos
Caderinas/genética , Epilepsia/genética , Epilepsia/patologia , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Pré-Escolar , Cromossomos Humanos X/genética , Epilepsia/complicações , Epilepsia/reabilitação , Humanos , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/reabilitação , Masculino
9.
Autoimmunity ; 51(4): 175-182, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29950118

RESUMO

OBJECTIVE: In literature, the importance of X-linked gene dosage as a contributing factor for autoimmune diseases is generally assumed. However, little information is available on the frequency of humoral endocrine organ-specific autoimmunity in X-chromosome aneuploidies. In our preliminary study, we investigated the endocrine organ-specific humoral autoimmunity relative to four different organ-specific autoimmune diseases in a group of adult 47,XXY KS patients and in adults 46,XY control males (type 1 diabetes, T1DM; Addison's disease, AD; Hashimoto thyroiditis, HT; autoimmune chronic atrophic gastritis, AG). The aim of the present study is to evaluate the frequency of autoantibodies (Abs) specific for T1DM, AD, HT, and AG in rarer higher grade X-chromosome aneuploidies (HGA) and in 47,XXY children. DESIGN AND METHODS: Samples from 192 Caucasian patients with an X-chromosome aneuploidy (176 patients (55 children, 121 adults) with 47,XXY karyotype (KS patients) and 16 HGA patients (eight children, eight adults)) recruited from Sapienza, University of Rome (2007-2017) were tested for Abs specific for T1DM (insulin-Abs, GAD-Abs, IA-2-Abs, Znt8-Abs), HT (TPO-Abs), AD (21-OH-Abs), and AG (APC-Abs). The results were compared to those found in 213 46,XY control subjects (96 children, 117 adults). RESULTS: Altogether humoral organ-specific immunoreactivity was found in 13% of KS and HGA patients, with a significantly higher frequency than in the controls (p=.008). Almost 19% of HGA patients were positive for at least one of the organ-specific Abs investigated compared to 12.5% of KS patients. The frequency of the overall immunoreactivity was higher in KS children than in KS adults. The frequency of diabetes-specific Abs was significantly higher in the patient cohort than in controls (p=.005). Thyroid- and gastric-specific autoimmunity was also found in KS and HGA patients, while adrenal-specific immunoreactivity was rare. CONCLUSIONS: These results suggest for the first time that the risk of endocrine organ-specific humoral autoimmunity progressively increases with the severity of X-chromosome polisomy. The screening for diabetes-, thyroid-, and gastric-specific autoimmunity should be considered in clinical practice for identifying rare and classic X-chromosome aneuploid patients at risk of developing organ-specific autoimmune diseases.


Assuntos
Doença de Addison/imunologia , Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Gastrite Atrófica/imunologia , Doença de Hashimoto/imunologia , Síndrome de Klinefelter/imunologia , Doença de Addison/sangue , Doença de Addison/genética , Doença de Addison/patologia , Adolescente , Adulto , Idoso , Especificidade de Anticorpos , Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Gastrite Atrófica/sangue , Gastrite Atrófica/genética , Gastrite Atrófica/patologia , Doença de Hashimoto/sangue , Doença de Hashimoto/genética , Doença de Hashimoto/patologia , Humanos , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Masculino , Pessoa de Meia-Idade , Trissomia/imunologia
10.
Cell Death Dis ; 9(6): 586, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789566

RESUMO

The most common human sex chromosomal disorder is Klinefelter syndrome (KS; 47,XXY). Adult patients with KS display a diverse phenotype but are nearly always infertile, due to testicular degeneration at puberty. To identify mechanisms causing the selective destruction of the seminiferous epithelium, we performed RNA-sequencing of 24 fixed paraffin-embedded testicular tissue samples. Analysis of informative transcriptomes revealed 235 differentially expressed transcripts (DETs) in the adult KS testis showing enrichment of long non-coding RNAs, but surprisingly not of X-chromosomal transcripts. Comparison to 46,XY samples with complete spermatogenesis and Sertoli cell-only-syndrome allowed prediction of the cellular origin of 71 of the DETs. DACH2 and FAM9A were validated by immunohistochemistry and found to mark apparently undifferentiated somatic cell populations in the KS testes. Moreover, transcriptomes from fetal, pre-pubertal, and adult KS testes showed a limited overlap, indicating that different mechanisms are likely to operate at each developmental stage. Based on our data, we propose that testicular degeneration in men with KS is a consequence of germ cells loss initiated during early development in combination with disturbed maturation of Sertoli- and Leydig cells.


Assuntos
Diferenciação Celular/genética , Perfilação da Expressão Gênica , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Células Intersticiais do Testículo/patologia , Células de Sertoli/patologia , Testículo/patologia , Adulto , Estudos de Casos e Controles , Humanos , Células Intersticiais do Testículo/metabolismo , Masculino , Puberdade/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células de Sertoli/metabolismo , Transcriptoma/genética
11.
Andrologia ; 50(7): e13024, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29665107

RESUMO

Klinefelter syndrome is a condition in which a male patient has one Y chromosome and one or more extra X chromosomes. It is the most common sex chromosome disorder. Klinefelter syndrome is distinguished by many clinical features, such as infertility, high gonadotropin and low testosterone levels, increased height, and sparse body and facial hair. We report the case of a 32-year-old man who visited our hospital complaining of male infertility. Semen analysis showed azoospermia, and chromosomal analysis revealed a 47,XY,i(X)(q10) karyotype, which is a rare variant of Klinefelter syndrome. No spermatozoon was found on microdissection testicular sperm extraction, and the testis biopsy histology showed only Sertoli cells and hyalinised seminiferous tubules. 47,XY, i(X)(q10) has an additional isochromosome made of the long arm of the X chromosome, which shares some features of classical Klinefelter syndrome in many aspects, but patients are usually shorter than average height and have normal intelligence. In addition, to the best of our knowledge, no successful sperm extractions from 47,XY, i(X)(q10) patients were reported in the literature. The reports of patients who have undergone microdissection testicular sperm extraction are very rare. Further reports and studies of this chromosomal abnormality are needed.


Assuntos
Azoospermia/genética , Aberrações Cromossômicas , Cromossomos Humanos Y/genética , Síndrome de Klinefelter/genética , Adulto , Azoospermia/diagnóstico , Azoospermia/patologia , Biópsia , Humanos , Cariótipo , Cariotipagem , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/patologia , Masculino , Testículo/patologia
12.
Endocrine ; 61(2): 327-335, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29696556

RESUMO

PURPOSE: To assess different aspects of bone damage in untreated adult patients with Klinefelter Syndrome (KS) before and during testosterone replacement therapy (TRT). METHODS: Fifteen untreated hypogonadal men with KS and 26 control subjects (C) matched for age and BMI were recruited. Sex hormone levels were measured in all subjects. Lumbar spine (LS) and femoral (neck: FN and total hip: TH) bone mineral density (BMD), trabecular bone score (TBS), hip structure analysis (HSA) and fat measures (percentage of fat mass, android/gynoid ratio and visceral adipose tissue) were evaluated by DEXA. In KS patients, blood analysis and DEXA measurements were assessed at baseline and repeated yearly for three years during TRT. RESULTS: Fat measures were significantly higher in KS than C (p < 0.01). In contrast, mean LS, FN and TH BMD were significantly reduced in KS compared to C (p < 0.01), while there was no difference in TBS. HSA revealed a significantly lower cortical thickness and significantly higher buckling ratio in KS compared to C at all femoral sites (p < 0.01). In KS patients, TRT significantly increased BMD at LS only, but did not improve TBS and HSA parameters. Fat measures were inversely associated with TBS values, and TRT did not influence this relationship. CONCLUSIONS: In untreated hypogonadal men with KS, lumbar and femoral BMD was reduced, and femoral bone quality was impaired. Adiposity seemed to have a detrimental effect on lumbar bone microarchitecture, as indirectly evaluated by TBS. However, TRT failed to remedy these negative effects on bone.


Assuntos
Osso e Ossos/efeitos dos fármacos , Terapia de Reposição Hormonal , Hipogonadismo/tratamento farmacológico , Síndrome de Klinefelter/tratamento farmacológico , Testosterona/uso terapêutico , Adulto , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Estudos de Casos e Controles , Fêmur/efeitos dos fármacos , Fêmur/patologia , Colo do Fêmur/efeitos dos fármacos , Colo do Fêmur/patologia , Seguimentos , Humanos , Hipogonadismo/complicações , Hipogonadismo/patologia , Síndrome de Klinefelter/metabolismo , Síndrome de Klinefelter/patologia , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
13.
Andrologia ; 50(5): e13004, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29512178

RESUMO

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.


Assuntos
Fertilidade/genética , Síndrome de Klinefelter/patologia , Espermatogênese/genética , Espermatozoides/patologia , Testículo/patologia , Adulto , Biópsia , Hormônio Foliculoestimulante/sangue , Humanos , Inibinas/sangue , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/genética , Hormônio Luteinizante/sangue , Masculino , Recuperação Espermática , Testosterona/sangue
14.
J Clin Endocrinol Metab ; 103(5): 2033-2041, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29452406

RESUMO

Context: The regulation of bone mass by the testis is a well-recognized mechanism, but the role of Leydig-specific marker insulin-like 3 peptide (INSL3) on the most abundant bone cell population, osteocytes, is unknown. In this study, we aimed to investigate the relationship between INSL3 and sclerostin, an osteocyte-specific protein that negatively regulates bone formation. Design: Serum sclerostin and INSL3 levels were evaluated in Klinefelter syndrome (KS) and healthy controls. In vitro effect of INSL3 on sclerostin production was evaluated in human cultured osteocytes. Patients: A total of 103 KS patients and 60 age- and sex-matched controls were recruited. Main Outcome Measures: Serum sclerostin and INSL3 levels were assessed by enzyme-linked immunosorbent assay. Osteocytes were isolated by fluorescence-assisted cell sorting. Sclerostin expression was evaluated by western blot, immunofluorescence, and reverse transcription polymerase chain reaction. Measurement of bone mineral density was done by dual-energy X-ray absorptiometry at lumbar spine (L1-L4) and femoral neck. Results: Sclerostin levels were significantly increased in KS subjects, and negatively correlated with INSL3 levels in both cohorts and with bone mineral density in the KS group. Stimulation of cultured osteocytes with INSL3 at 10-7 M significantly decreased both sclerostin messenger RNA and protein expression. Conclusions: We report a negative association between the testicular hormone INSL3 and the osteocytic negative regulator of bone formation, sclerostin. We further explored this association in vitro and showed that INSL3 was able to reduce sclerostin expression. These results add further knowledge on the emerging role of sclerostin as a therapeutic target for osteoporosis treatment.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Síndrome de Klinefelter/metabolismo , Osteócitos/metabolismo , Proteínas/metabolismo , Proteínas/farmacologia , Adulto , Proteínas Morfogenéticas Ósseas/sangue , Proteínas Morfogenéticas Ósseas/genética , Estudos de Casos e Controles , Células Cultivadas , Feminino , Expressão Gênica/efeitos dos fármacos , Marcadores Genéticos/genética , Humanos , Insulina/sangue , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Masculino , Pessoa de Meia-Idade , Osteócitos/efeitos dos fármacos , Osteócitos/patologia , Hormônio Paratireóideo/farmacologia , Estudos Retrospectivos , Adulto Jovem
15.
Sci Rep ; 7(1): 13130, 2017 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-29030589

RESUMO

Klinefelter Syndrome (KS), the most common chromosomal disorder in men (47,XXY), is associated with numerous comorbidities. Based on a number of isolated case reports, we performed the first systematic and comprehensive evaluation of eye health in KS patients with a focus on ocular structure and vascularization. Twenty-one KS patients and 26 male and 38 female controls underwent a variety of non-invasive examinations investigating ocular morphology (examination of retinal thickness, optic nerve head, and cornea) and function (visual field testing and quantification of ocular vessel density by optical coherence tomography angiography). In comparison to healthy controls, KS patients exhibited a smaller foveal avascular zone and a decreased retinal thickness due to a drastically thinner outer nuclear layer. The cornea of KS patients showed a decreased peripheral thickness and volume. In perimetry evaluation, KS patients required brighter stimuli and gave more irregular values. KS patients show an ocular phenotype including morphological and functional features, which is very likely caused by the supernumerary X chromosome. Thus, KS should not be limited to infertility, endocrine dysfunction, neurocognitive and psychosocial comorbidities. Defining an aberrant ocular morphology and function, awareness for possible eye problems should be raised.


Assuntos
Cromossomos Humanos X/genética , Síndrome de Klinefelter/patologia , Córnea/metabolismo , Córnea/patologia , Feminino , Humanos , Síndrome de Klinefelter/genética , Masculino , Disco Óptico/metabolismo , Disco Óptico/patologia , Retina/metabolismo , Retina/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia
16.
Indian J Pathol Microbiol ; 60(3): 424-426, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28937389

RESUMO

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.


Assuntos
Incontinência Pigmentar/complicações , Incontinência Pigmentar/diagnóstico , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/diagnóstico , Pré-Escolar , Humanos , Quinase I-kappa B/genética , Incontinência Pigmentar/patologia , Síndrome de Klinefelter/patologia , Masculino
17.
J Pediatr Endocrinol Metab ; 30(7): 797-803, 2017 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-28672740

RESUMO

BACKGROUND: Achondroplasia (ACH), an autosomal dominant skeletal dysplasia, occurs in approximately 1:20,000 births. On the other hand, 47,XXY aneuploidy (Klinefelter syndrome [KS]) is the most common sex chromosome disorder, with a prevalence of approximately 1:600 males. To the best of our knowledge, only five cases of patients presenting both ACH and KS have been reported to date in the international literature. However, none of these cases has been longitudinally followed during the entire childhood. CASE PRESENTATION: We report a male patient with ACH and KS, diagnosed in early infancy because of his typical phenotype of ACH. The diagnosis was confirmed by molecular analysis revealing a de novo heterozygous 1138 G-to-A mutation of the FGFR3 gene. During his first assessment, a karyotype was performed, which also revealed coexistence of KS. He was followed by our pediatric endocrinology team until the age of 16 years, then he was gradually transferred to adult endocrine care. CONCLUSIONS: This is the first reported case with both conditions that was diagnosed in infancy and was longitudinally followed by a pediatric endocrinology team regularly, from infancy to late adolescence. With a typical phenotype of ACH, it is striking and noteworthy that he did not develop the classical endocrine complications of a child with KS, neither did he necessitate testosterone supplementation during his pubertal development, due to his normal virilization and testosterone levels.


Assuntos
Acondroplasia/patologia , Regulação da Expressão Gênica no Desenvolvimento , Síndrome de Klinefelter/patologia , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acondroplasia/genética , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Cariotipagem , Síndrome de Klinefelter/genética , Masculino , Prognóstico
18.
Sci Rep ; 7(1): 3358, 2017 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-28611373

RESUMO

Klinefelter Syndrome (KS) is the most common chromosomal disorder in men leading to non-obstructive azoospermia. Spermatozoa can be found by TESE in about 50% of adults with KS despite severe testicular degeneration. We evaluated AR variations and polymorphism length in 135 non-mosaic KS patients, aimed to find possible correlation with clinical features, sex hormones and sperm retrieval. Among 135 KS patients we found AR variations in eight subjects (5.9%). All variations but one caused a single amino acid substitution. Four variations P392S, Q58L, L548F, A475V found in six patients had been previously described to be associated with different degrees of androgen insensitivity. Moreover we observed in two patients Y359F and D732D novel variations representing respectively a missense variation and a synonymous variation not leading to amino acid substitution. All the Klinefelter patients with AR gene variations were azoospermic. Spermatozoa were retrieved with TESE for two men (40%), sperm retrieval was unsuccessful in other 3 patients. This is the only study reporting AR variations in KS patients. Relevant clinical differences not emerged between AR mutated and not AR mutated KS patients, but does each variation play an important role in the trasmission to the offspring obtained by ART in this patients?


Assuntos
Azoospermia/patologia , Biomarcadores Tumorais/genética , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Mutação , Polimorfismo de Nucleotídeo Único , Receptores Androgênicos/genética , Adolescente , Adulto , Azoospermia/genética , Seguimentos , Humanos , Síndrome de Klinefelter/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Recuperação Espermática , Adulto Jovem
19.
Urol J ; 14(3): 3081-3084, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28537047

RESUMO

PURPOSE: To identify any relationship between known reasons of male infertility and 2D:4D ratio. MATERIALS AND METHODS: A total of 371 males were included in the study. The cases were grouped into 6 groups including sperm count < 5 million/mL, sperm count ≥ 5 million/mL, Klinefelter Syndrome, hypogonadotropic hypogonadism, vasal agenesis and control. Groups were compared with each other in terms of 2D:4D ratios and groups with a 2D:4D ratios below 1 and equal/above 1 were compared. RESULTS: The greatest ratios were in the vasal agenesis and hypogonadotropic hypogonadism groups and analysis of the data with logistic regression analysis showed that there was a significant difference in terms of 2D:4D ratios for these groups when comparing with control group. The other groups showed no statistically significantdifferences. CONCLUSION: The results of the present study showed some significant difference between 2D:4D ratios for the subgroups of the fertile and infertile cases. Although, 2D:4D ratio is not an unaccompanied parameter to reveal causes of male infertility, it can be associated with some situations that are related with male infertility.


Assuntos
Dedos/anatomia & histologia , Infertilidade Masculina/patologia , Contagem de Espermatozoides , Azoospermia/patologia , Humanos , Hipogonadismo/patologia , Síndrome de Klinefelter/patologia , Masculino , Oligospermia/patologia , Estudos Prospectivos , Ducto Deferente/anormalidades
20.
Hum Mol Genet ; 26(7): 1219-1229, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28369266

RESUMO

Klinefelter syndrome (KS) (47,XXY) is the most common male sex chromosome aneuploidy. Diagnosis and clinical supervision remain a challenge due to varying phenotypic presentation and insufficient characterization of the syndrome. Here we combine health data-driven epidemiology and molecular level systems biology to improve the understanding of KS and the molecular interplay influencing its comorbidities. In total, 78 overrepresented KS comorbidities were identified using in- and out-patient registry data from the entire Danish population covering 6.8 million individuals. The comorbidities extracted included both clinically well-known (e.g. infertility and osteoporosis) and still less established KS comorbidities (e.g. pituitary gland hypofunction and dental caries). Several systems biology approaches were applied to identify key molecular players underlying KS comorbidities: Identification of co-expressed modules as well as central hubs and gene dosage perturbed protein complexes in a KS comorbidity network build from known disease proteins and their protein-protein interactions. The systems biology approaches together pointed to novel aspects of KS disease phenotypes including perturbed Jak-STAT pathway, dysregulated genes important for disturbed immune system (IL4), energy balance (POMC and LEP) and erythropoietin signalling in KS. We present an extended epidemiological study that links KS comorbidities to the molecular level and identify potential causal players in the disease biology underlying the identified comorbidities.


Assuntos
Cromossomos Humanos X/genética , Dosagem de Genes/genética , Síndrome de Klinefelter/genética , Biologia de Sistemas , Aneuploidia , Comorbidade , Dinamarca , Cárie Dentária/genética , Cárie Dentária/patologia , Humanos , Interleucina-4/genética , Janus Quinase 1/genética , Síndrome de Klinefelter/epidemiologia , Síndrome de Klinefelter/patologia , Masculino , Hipófise/metabolismo , Hipófise/patologia , Pró-Proteína Convertases/genética , Fatores de Transcrição STAT/genética , Testosterona/genética
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