Macular hypoplasia and high myopia in 48, xxyy syndrome: a unique case of 48, xxyy syndrome that presents with high myopia and macular dysplasia.

BACKGROUND: Among sex chromosome aneuploidies, 48, XXYY syndrome is a rare variant. This condition is marked by the existence of an additional X and Y chromosome in males, leading to a diverse range of physical, neurocognitive, behavioral, and psychological manifestations. Typical characteristics include a tall stature and infertility. Other phenotypes include congenital heart defects, skeletal anomalies, tremors, obesity, as well as the potential for type 2 diabetes and/or peripheral vascular disease. CASE PRESENTATION: A 6-year-old boy, who had been experiencing progressive vision deterioration in both eyes for the past two years, presented with a history of poor vision, delayed motor skills. The patient was diagnosed with micropenis in the pediatric outpatient clinic. Sparse hair, an unusually tall stature and craniofacial dysmorphology characterized by ocular hypertelorism, depressed nasal bridge, and epicanthic folds were observed. Comprehensive ophthalmic examination revealed high myopia and grade 3 macular hypoplasia. Diagnostic investigations including karyotype analysis and whole-exome sequencing identified an anomalous male karyotype comprising two X and two Y chromosomes, confirming a diagnosis of 48, XXYY syndrome. CONCLUSIONS: This study underscores the rare association of high myopia and grade 3 macular dysplasia with 48, XXYY syndrome. To our knowledge, this case marks the first recorded instance of macular dysplasia in a patient with 48, XXYY syndrome. This novel finding enhances our understanding of this syndrome's phenotypic variability.

Mediastinal Germ-cell Tumors Relapse in a Male With Klinefelter Syndrome. Is Longer Surveillance Needed?

Germ cell tumors (GCTs) are a heterogeneous group of pediatric cancers. In up to one-third of male patients, a primary mediastinal location is associated with the presence of Klinefelter syndrome (KS). We describe a case of mediastinal GCT in a patient, with unacknowledged KS, that presented a relapse 7 years from diagnosis, that is, 2 years after the end of the follow-up program usually recommended for patients with GCT. There are no recommendations for screening for KS in patients with mediastinal GCT and there are no specific guidelines for surveillance of GCT in KS patients. Our experience suggests that KS should be suspected in patients with mediastinal GCT, and a longer follow-up plan should be implemented when GCT occurs in patients with KS.

Serum Lipocalin-2 Levels as a Biomarker in Pre- and Post-Pubertal Klinefelter Syndrome Patients: A Pilot Study.

Klinefelter syndrome (KS) is a male genetic disease caused by the presence of an extra X chromosome, causing endocrine disorders mainly responsible for a high rate of infertility and metabolic disorders in adulthood. Scientific research is interested in identifying new biomarkers that can be predictive or prognostic of alterations strictly connected to KS. Lipocalin-2 (LCN-2, also known as NGAL) is a small protein initially identified within neutrophils as a protein related to innate immunity. Serum LCN-2 estimation seems to be a useful tool in predicting the metabolic complications caused by several pathological conditions. However, little is known about its potential role in infertility conditions. The present pilot study aims to investigate the presence of LCN-2 in the serum of a group of pre-pubertal and post-pubertal children affected by KS, compared to healthy controls. We demonstrated for the first time the presence of elevated levels of LCN-2 in the serum of KS patients, compared to controls. This increase was accompanied, in pre-pubertal KS patients, by the loss of correlation with LH and HDL, which instead was present in the healthy individuals. Moreover, in all KS individuals, a positive correlation between LCN-2 and inhibin B serum concentration was found. Despite the limited size of the sample analyzed, our preliminary data encourage further studies to confirm the findings and to extend the study to KS adult patients, to verify the predictive/prognostic value of LCN-2 as new biomarker for metabolic diseases and infertility associated with the pathology.

A rare case of adult-onset spastic paraparesis associated with Klinefelter syndrome.

REPORT: The rare association of Klinefelter syndrome and the clinical presentation of a late onset chronic progressive spastic paresis. CLINICAL PRESENTATION AND GENETICS: An infertile, 61-year-old man, presented with late adult onset of gait problems, deep muscle pain, and bladder problems. He presented for the first time, years after onset with a spastic paraparesis with high arched feet. His parents had already died, but the patient described high arched feet with his mother. There is no further certain information about the parents. After thorough investigation, an additional X chromosome was found, whereafter the diagnosis of Klinefelter syndrome could be made. Other acquired and genetic causes for spastic paraparesis or hereditary motor neuropathy are excluded. CONCLUSION: This rare case, together with three other literature reports by Sasaki (Intern Med 58(3):437-440, 2019), Sajra (Med Arh 61(1):52-53, 2007) and Matsubara et al., (J Neurol Neurosurg Psychiatry 57(5):640-642, 1994). suggests that Klinefelter syndrome can be associated with spastic paraparesis, besides the other various neuropsychiatric symptoms that are more commonly described.

Detection of chromosomal aneuploidy in ancient genomes.

Ancient DNA is a valuable tool for investigating genetic and evolutionary history that can also provide detailed profiles of the lives of ancient individuals. In this study, we develop a generalised computational approach to detect aneuploidies (atypical autosomal and sex chromosome karyotypes) in the ancient genetic record and distinguish such karyotypes from contamination. We confirm that aneuploidies can be detected even in low-coverage genomes ( ~ 0.0001-fold), common in ancient DNA. We apply this method to ancient skeletal remains from Britain to document the first instance of mosaic Turner syndrome (45,X0/46,XX) in the ancient genetic record in an Iron Age individual sequenced to average 9-fold coverage, the earliest known incidence of an individual with a 47,XYY karyotype from the Early Medieval period, as well as individuals with Klinefelter (47,XXY) and Down syndrome (47,XY, + 21). Overall, our approach provides an accessible and automated framework allowing for the detection of individuals with aneuploidies, which extends previous binary approaches. This tool can facilitate the interpretation of burial context and living conditions, as well as elucidate past perceptions of biological sex and people with diverse biological traits.

Klinefelter syndrome presenting as metastatic bilateral breast cancer: missed diagnostic opportunities.

Klinefelter syndrome (KS) is the most common cause of primary hypogonadism in male patients; however, the diagnosis of KS is frequently delayed or missed. This delay can lead to undesirable outcomes for patients, especially considering that individuals with KS have a higher risk of developing specific malignancies, including breast cancer, non-Hodgkin's lymphoma and mediastinal germ cell tumours. We present a case of a male patient in his 60s, where the established diagnosis of metastatic bilateral breast cancer prompted us to investigate and subsequently confirm a diagnosis of KS. This case highlights the diagnostic challenges of KS and emphasises the unfavourable consequences of a delayed diagnosis. We aim to raise awareness and enhance physicians' understanding of KS and its non-reproductive manifestations, with a view to promote early recognition and improve patient outcomes.

Individuals with numerical and structural variations of sex chromosomes: interdisciplinary management with focus on fertility potential.

Diagnosis and management of individuals who have differences of sex development (DSD) due to numerical or structural variations of sex chromosomes (NSVSC) remains challenging. Girls who have Turner syndrome (45X) may present with varying phenotypic features, from classical/severe to minor, and some remain undiagnosed. Boys and girls who have 45,X/46,XY chromosomal mosaicism may have Turner syndrome-like features and short stature; therefore, unexplained short stature during childhood requires karyotype analysis in both sexes, particularly if characteristic features or atypical genitalia are present. Many individuals with Klinefelter syndrome (47XXY) remain undiagnosed or are only diagnosed as adults due to fertility problems. Newborn screening by heel prick tests could potentially identify sex chromosome variations but would have ethical and financial implications, and in-depth cost-benefit analyses are needed before nationwide screening can be introduced. Most individuals who have NSVSC have lifelong co-morbidities and healthcare should be holistic, personalized and centralized, with a focus on information, psychosocial support and shared decision-making. Fertility potential should be assessed individually and discussed at an appropriate age. Oocyte or ovarian tissue cryopreservation is possible in some women who have Turner syndrome and live births have been reported following assisted reproductive technology (ART). Testicular sperm cell extraction (TESE) is possible in some men who have 45,X/46,XY mosaicism, but there is no established protocol and no reported fathering of children. Some men with Klinefelter syndrome can now father a child following TESE and ART, with multiple reports of healthy live births. Children who have NSVSC, their parents and DSD team members need to address possibilities and ethical questions relating to potential fertility preservation, with guidelines and international studies still needed.

Hypergonadotropic hypogonadism and chromosomal aberrations: clinical heterogeneity and implications on the health of elderly men, case series.

BACKGROUND: Hypogonadism in older men is often considered as late onset hypogonadism. However, this clinical condition results from primary testicular failure which could be of genetic origin with Klinefelter syndrome being the most common chromosomal abnormality associated with it. CASE PRESENTATION: We report a heterogeneous group of cases who were diagnosed with hypergonadotropic hypogonadism in their adulthood and were found to have rare chromosomal aberrations. All were elderly men (in their 70 s and 80 s) for whom the diagnosis was made during the evaluation of incidental symptoms suggestive of endocrinopathy. The first had hyponatremia; the other two had gynaecomastia and features of hypogonadism noted during admission for various acute medical problems. With respect to their genetic results; the first had a male karyotype with balanced reciprocal translocation between the long arm of chromosome 4 and the short arm of chromosome 7. The second case had a male karotype with one normal X chromosome and an isochrome for the short arm of the Y chromosome. The third case was an XX male with unbalanced translocation between the X & Y chromosomes with retention of the SRY locus. CONCLUSION: Hypergonadotrophic hypogonadism in the elderly, may be due to chromosomal aberrations, resulting in heterogeneous and diverse clinical phenotypes. Vigilance must be exercised when seeing cases with subtle clinical findings. This report suggests that in selected cases of adult hypergonadotropic hypogonadism, chromosomal analysis may be indicated.

Klinefelter syndrome: The characterization of the clinical and sociological features of 51 patients.

INTRODUCTION: Klinefelter syndrome is the most frequently found aneuploidy among male patients. Its clinical presentation is very heterogeneous, and thus poses a challenge for a timely diagnosis. METHODS: A retrospective study was carried out with 51 consecutively selected patients diagnosed with Klinefelter Syndrome from Jan/2010 to Dec/2019. The karyotypes were identified using high resolution GTL banding at the Genetics Department. Multiple clinical and sociological parameters were studied by collecting data from the clinical records. RESULTS: 44 (86%) of the 51 patients presented a classical karyotype (47,XXY) and 7 (14%) showed evidence of mosaicism. The mean age at diagnosis was 30.2±14.3 years old. Regarding the level of education (N=44), 26 patients (59.1%) had no secondary education, with 5 (11.4%) patients having concluded university studies. Almost two thirds of the sample revealed learning difficulties (25/38) and some degree of intellectual disability was present in 13.6% (6/44). Half of the patients were either non-qualified workers (19.6%) or workers in industry, construction, and trades (30.4%), which are jobs that characteristically require a low level of education. The proportion of unemployed patients was 6.5%. The main complaints were infertility (54.2%), followed by hypogonadism-related issues (18.7%) and gynecomastia (8.3%). 10 patients (23.8%, N=42) were biological parents. With regards the question of fertility, assisted reproductive techniques were used in 39.6% of the studied subjects (N=48), with a success rate (a take home baby) of 57.9% (11/19), 2 with donor sperm and 9 with the patients' own gametes. Only 41% of the patients (17/41) were treated with testosterone. CONCLUSION: This study identifies the most important clinical and sociological findings of Klinefelter syndrome patients that should be considered when deciding workout and disease management.

Klinefelter's Syndrome with Tremors, Ataxia and Parkinsonism.

Klinefelter's syndrome (KS) is the most common cause of hypogonadism in men. Essential tremor (ET) and parkinsonism have been reported in KS, but ataxia, which has been commonly reported with other causes of hypogonadism, is very rare in KS. Orthostatic tremor has not been reported. We present a case with multiple movement disorders, including gait ataxia, essential-type tremor, rest tremor, orthostatic tremor and parkinsonism.

[Clinicopathological characteristics of Klinefelter syndrome: a testicular biopsy analysis of 87 cases].

Objective: To investigate the clinicopathological characteristics of testicular biopsies from Klinefelter syndrome (KS) patients. Methods: The testicular biopsy specimens of 87 patients with KS (a total of 107 biopsy specimens) were collected from the Department of Pathology, Peking University Third Hospital, Beijing, China from January 2017 to July 2022. All patients were diagnosed as KS by peripheral blood karyotyping analysis. The testicular histopathologic features, testicular volume and hormone levels were evaluated retrospectively. The histopathologic analysis was used to assess the quantity and morphology of Leydig cells, the spermatogenic state of seminiferous tubules, the thickening of the basement membrane of seminiferous tubules and the changes of stroma. Results: Leydig cell proliferative nodules were seen in 95.3% (102/107) of KS testicular biopsy tissues. The eosinophilic inclusion bodies and lipofuscin in Leydig cells were found in 52.3% (56/107) and 57.9% (62/107) of specimens, respectively. The Sertoli cell only seminiferous tubules and the hyalinized tubules were found in 66.4% (71/107) and 76.6% (82/107) of the examined tissues, respectively. The tubules with complete spermatogenic arrest were found in 15.9% (17/107) of specimens, and 5.6% (6/107) of the specimens showed low spermatogenesis or incomplete spermatogenic arrest. In 85.0% (91/107) of the specimens, increased thick-walled small vessels with hyaline degeneration were identified. Conclusions: The most common features of KS testicular specimens are Leydig cell proliferative nodules, hyaline degeneration of seminiferous tubules and proliferation of thick-walled blood vessels. Testicular biopsy specimens of KS are rare. The pathologists can make a tentative diagnosis of KS based on the histological findings, combined with the ultrasound and laboratory results, which is helpful for further diagnosis and treatment of KS.

Combined Alport syndrome, Klinefelter syndrome and Fanconi syndrome in a Chinese boy.

Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant (XLAS) is the major inheritance form, accounting for almost 80% of the cases, caused by mutations in COL4A5 genes. Klinefelter syndrome (KS) is the most common genetic cause of human male gonadal dysgenesis. AS and KS are both rare disease, there are only three cases of combined AS and KS in the literatures. Fanconi syndrome (FS) caused by AS is also very rare. We report here the first case combined AS, KS and FS in a Chinese boy. We suggest that the severe renal phenotype and FS might be due to the two homozygous COL4A5 variants in our boy, and cases of AS combined KS will be good research objects for X chromosome inactivation.

State-wide increase in prenatal diagnosis of klinefelter syndrome on amniocentesis and chorionic villus sampling: Impact of non-invasive prenatal testing for sex chromosome conditions.

BACKGROUND: To analyze population-based trends in the prenatal diagnosis of sex chromosome aneuploidy (SCA) since the availability of non-invasive prenatal testing (NIPT). METHODS: Retrospective state-wide data for all prenatal diagnoses performed <25 weeks gestation from 2005 to 2020 in Victoria, Australia. Non-invasive prenatal testing became locally available from 2012. The prenatal diagnosis rates of SCA as proportions of all prenatal diagnostic tests and all births were calculated. Statistical significance was assessed with the χ2 test for trend, with p < 0.05 considered significant. RESULTS: 46,518 amniocentesis and chorionic villus sampling were performed during the study period, detecting 617 SCAs. There was a significant increase in the rate of prenatal SCAs from 5.8 per 10,000 births in 2005 to 8.7 per 10,000 births in 2020 (p < 0.0001). This increase was predominantly due to 47,XXY cases, 91% of which were ascertained via positive NIPT for this condition in 2020. The prenatal diagnosis rate of 47,XXY significantly increased from 0.8 per 10,000 births in 2005 to 4.3 per 10,000 births in 2020 (p < 0.0001). CONCLUSION: Screening for SCAs using NIPT has directly led to an increase in their prenatal diagnosis on a population-wide basis, especially 47,XXY. This has implications for clinician education, genetic counselling, and pediatric services.

Content Analysis of Social Support, and Disease Framing of Klinefelter Syndrome and Down Syndrome: Social Support, Framing and Decision Tendencies.

The Internet plays a crucial role for people searching for health information. In the context of parents faced with a prenatal diagnosis of a chromosomal abnormality, Internet-based resources convey critical information and attitudes that bear on the process of healthcare decision-making. In this study, we collected and analyzed 268 websites for Klinefelter syndrome and Down syndrome, which are two of the most common genetic conditions marked by an abnormal number of chromosomes. While these two syndromes are quite different in terms of their associated symptoms and health consequences, they are commonly screened for, have similar incidence rates, and parents who are presented with prenatal diagnosis of the two conditions terminate pregnancies at similar rates. The study found substantial differences in framings of information, and social support available online for Klinefelter syndrome and Down syndrome. This study's key finding supports the argument that social support and framing are important mechanisms that mediate online information and perceptions of information utility, hope and decision tendency. The study extends theories and literature related to information framing in a mass media context, social support, and cognitive information processing and applies to investigating online health information, social support and perceptions.

Prenatal phenotype of 47, XXY (Klinefelter syndrome).

OBJECTIVE: There is a paucity of knowledge regarding the prenatal presentation of Klinefelter syndrome, or 47, XXY. Accurate prenatal counseling is critical and in utero diagnosis is currently limited by a poor understanding of the prenatal phenotype of this condition. METHODS: This is a case series of fetuses with cytogenetically confirmed 47, XXY in the prenatal period or up to age 5 years, with prenatal records available for review from four academic institutions between 2006 and 2019. Ultrasound reports were reviewed in detail to assess for increased nuchal translucency and structural abnormalities. Additionally, we reviewed results of cell-free DNA and serum analyte testing when performed to inform our understanding of the detection of fetal 47, XXY through standard genetic screening tests. RESULTS: Forty-one cases with confirmed cytogenetic diagnosis of 47, XXY and prenatal records available for review were identified: 37 had a prenatal diagnosis and 4 had a postnatal diagnosis. Nuchal translucency was increased ≥3.0 mm in 23.1% (6/26) of cases with a documented measurement. In 29.2% (7/24) of cases with a second trimester anatomical ultrasound available for review, a fetal abnormality was identified (3 brain anomalies, 1 cardiac abnormality, 1 echogenic bowel, and 2 limb abnormalities). Among those who had cell-free DNA and serum analytes performed, 92.6% (25/27) and 36.3% (4/11) had an abnormal result respectively. CONCLUSION: This case series expands our knowledge of the prenatal presentation of 47, XXY by identifying first and second trimester fetal sonographic abnormalities. Prenatal identification of this condition enables accurate counseling, focused prenatal management, and early postnatal interventions to ameliorate some of the known complications.

Neuroimmune Dysregulation in Prepubertal and Adolescent Individuals Affected by Klinefelter Syndrome.

BACKGROUND: The syndrome Klinefelter syndrome (KS) is a genetic disorder due to an extra X chromosome in males. Many cases remain undiagnosed until the onset of major manifestations, which include hypergonadotropic hypogonadism and infertility. This condition is associated with many comorbidities that involve the cardiovascular, endocrine, and immune systems. Last but not the least, individuals with KS show a high risk of developing psychiatric and mood disorders in adult age. OBJECTIVE: While many studies are accessible on KS in adult individuals, the neuroinflammatory condition in adolescent and prepubertal KS individuals is not fully known. METHODS: Our study aims to evaluate in prepubertal and adolescent KS individuals, for the first time, the levels of the serum of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), cytokines having subtle roles in oxidative processes, and neuroinflammation with respect to the levels of TNF-α, TGF-ß, MCP-1, IL-1α, IL-2, IL-6, IL-10, and IL-12 and oxidative stress by employing free oxygen radicals defense and free oxygen radicals test. RESULTS: We found no changes in NGF and oxidative stress parameters, but BDNF decreased compared to healthy children. Quite interestingly, our data showed reduced levels of IL-2, IL-1α, IL- 12, IL-10, and IL-6 in prepubertal KS children. CONCLUSION: The present study discloses disrupted immune system and neurotrophin pathways in KS children.

Testicular microlithiasis in paediatric patients with Klinefelter syndrome from infancy till adolescence: early start of degenerative process in the testes-preliminary results.

To present the results of testicular ultrasonography supported by clinical and hormonal aspects in paediatric patients with Klinefelter syndrome (KS). Prospective analysis of medical files of 20 patients diagnosed with KS between 2016 and 2022. Assessed data included analysis of causes of referral, ultrasound, and clinical characterisation with hormonal evaluation of serum FSH, LH, testosterone, inhibin B, and anti-Müllerian hormone. Non-mosaic Klinefelter syndrome (47, XXY) was diagnosed in 65% of cases (13/20) by the geneticist (including 7 cases prenatally), in 25% (5/20) by the endocrinologist and in 10% (2/20) by the hematologist. Ultrasound assessment revealed bilateral testicular microlithiasis (TM) in all patients. The youngest KS patient with TM was 3 months old. TM patterns have not changed during follow-ups of up to 6 years in any of the patients. In all KS patients markedly reduced echogenicity and in pubertal KS patients, also irregular echostructure of the testes was observed. The hormonal patterns observed in the study group were typical for those already described in KS. Sertoli and Leydig cell function was intact in prepubertal patients and deteriorated after the start of puberty. CONCLUSION: Although the degenerative process in the testicular tissue starts very early in the testes in KS and is reflected in morphological changes seen in ultrasonography, Sertoli and Leydig cell hormonal function is normal in prepubertal KS patients. WHAT IS KNOWN: • So far, normal Leydig and Sertoli cell function was observed in infants and prepubertal KS patients. WHAT IS NEW: • The morphological changes in the testes in KS may already be seen in early infancy.

Klinefelter syndrome: going beyond the diagnosis.

Although Klinefelter syndrome (KS) is common, it is rarely recognised in childhood, sometimes being identified with speech or developmental delay or incidental antenatal diagnosis. The only regular feature is testicular dysfunction. Postnatal gonadotropin surge (mini-puberty) may be lower, but treatment with testosterone needs prospective studies. The onset of puberty is at the normal age and biochemical hypogonadism does not typically occur until late puberty. Testosterone supplementation can be considered then or earlier for clinical hypogonadism. The size at birth is normal, but growth acceleration is more rapid in early and mid-childhood, with adult height greater than mid-parental height. Extreme tall stature is unusual. The incidence of adolescent gynaecomastia (35.6%) is not increased compared with typically developing boys and can be reduced or resolved by testosterone supplementation, potentially preventing the need for surgery. Around two-thirds require speech and language therapy or developmental support and early institution of therapy is important. Provision of psychological support may be helpful in ameliorating these experiences and provide opportunities to develop strategies to recognise, process and express feelings and thoughts. Boys with KS are at increased risk of impairment in social cognition and less accurate perceptions of social emotional cues. The concept of likely fertility problems needs introduction alongside regular reviews of puberty and sexual function in adolescents. Although there is now greater success in harvesting sperm through techniques such as testicular sperm extraction, it is more successful in later than in early adolescence. In vitro maturation of germ cells is still experimental.