PCDH19-related epilepsy in a male with Klinefelter syndrome: Additional evidence supporting PCDH19 cellular interference disease mechanism.

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.

Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT in Klinefelter syndrome.

Although the expected skeletal manifestations of testosterone deficiency in Klinefelter's syndrome (KS) are osteopenia and osteoporosis, the structural basis for this is unclear. The aim of this study was to assess bone geometry, volumetric bone mineral density (vBMD), microarchitecture, and estimated bone strength using high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with KS. Thirty-one patients with KS confirmed by lymphocyte chromosome karyotyping aged 35.8 ± 8.2 years were recruited consecutively from a KS outpatient clinic and matched with respect to age and height with 31 healthy subjects aged 35.9 ± 8.2 years. Dual-energy X-ray absorptiometry (DXA) and HR-pQCT were performed in all participants, and blood samples were analyzed for hormonal status and bone biomarkers in KS patients. Twenty-one KS patients were on long-term testosterone-replacement therapy. In weight-adjusted models, HR-pQCT revealed a significantly lower cortical area (p < 0.01), total and trabecular vBMD (p = 0.02 and p = 0.04), trabecular bone volume fraction (p = 0.04), trabecular number (p = 0.05), and estimates of bone strength, whereas trabecular spacing was higher (p = 0.03) at the tibia in KS patients. In addition, cortical thickness was significantly reduced, both at the radius and tibia (both p < 0.01). There were no significant differences in indices of bone structure, estimated bone strength, or bone biomarkers in KS patients with and without testosterone therapy. This study showed that KS patients had lower total vBMD and a compromised trabecular compartment with a reduced trabecular density and bone volume fraction at the tibia. The compromised trabecular network integrity attributable to a lower trabecular number with relative preservation of trabecular thickness is similar to the picture found in women with aging. KS patients also displayed a reduced cortical area and thickness at the tibia, which in combination with the trabecular deficits, compromised estimated bone strength at this site.

Effects of varying lengths of synthetic speech output on augmented requesting and natural speech production in an adolescent with Klinefelter syndrome.

Students with developmental disabilities and limited or no functional speech often use speech-generating devices. While the speech-output function of such devices is considered to have potential advantages, it is unclear whether the length of synthetic speech output influences augmented communication and natural speech production. To this end, we describe a two-phase study involving an adolescent with Klinefelter syndrome. In Phase 1, the frequency of augmented requests and natural speech were compared under three speech-output conditions (no-output, short-output, and long-output). In Phase 2, augmented requests in the long-output condition were no longer reinforced to determine if this would increase natural speech production. The presence and length of speech output did not influence the frequency of augmented requesting or natural speech production in Phase 1, but extinction of augmented requesting under the long-output condition in Phase 2 was associated with a significant increase in natural speech production under that condition, relative to the two other conditions. The implications of these findings for using speech-generating devices are discussed.

Postnatal screening for Klinefelter syndrome: is there a rationale?

UNLABELLED: Diagnosis of Klinefelter syndrome (KS) allows for timely beneficial interventions across the lifespan. Most cases currently remain undiagnosed because of low awareness of KS amongst health professionals, the hesitancy of men to seek medical attention and its variable clinical presentation. Given these barriers, population-based genetic screening provides an approach to comprehensive and early detection. We examine current evidence regarding risks and benefits of diagnosing KS at different ages. CONCLUSION: There is a lack of evidence regarding the influence of age at diagnosis on adult outcomes that can only be obtained through a pilot screening programme.

Hipogonadismo Masculino: Un Enfoque Sencillo y Práctico / Male Hipogonadism: A Simple and Practical Approach

El hipogonadismo masculino representa una diminución de la función testicular con una baja en la producción de testosterona e infertilidad. Puede ser ocasionado por un problema intrínseco de los testículos (hipogonadismo primario), una falla del eje hipotálamo-hipofisiario (hipogonadismo secundario) o una respuesta disminuída o ausente de los órganos blanco a los andrógenos (resistencia androgénica). Los síntomas del hipogonadismo incluyen la caída del vello corporal, disminución de la función sexual y cambios de la voz. Dependiendo de la edad de aparición puede presentarse atrofia testicular, hábito eunocoide y ginecomastia. A largo plazo puede presentarse osteoporosis. El diagnóstico se sospecha clínicamente y se establece con la demostración de concentraciones bajas de testosterona sanguínea. Si existe un aumento concomitante de las gonadotropinas circulantes, Hormona Folículo Estimulante y Hormona Luteinizante, se habla de un hipogonadismo primario; pero si ambas están disminuidas el hipogonadismo es secundario. Existen diferentes formas de testosterona para el tratamiento de los pacientes con hipogonadismo; la más común, es la testosterona de depósito (enantato o cipionato) la cual se inyecta por vía intramuscular. La terapia actual consiste en la administración de testosterona por vía transdérmica, no escrotal, obteniéndose una concentración normal de testosterona con preservación del ritmo cardíaco

[School and occupational history of 30 patients with Klinefelter's syndrome. Significance of early diagnosis]. / Schul- und Berufsanamnese bei 30 Patienten mit Klinefelter-Syndrom. Die Bedeutung der Frühdiagnose.

Thirty men aged 17-48 years with pure 47,XXY Klinefelter syndrome have been studied. The group was a positive selection diagnosed not on account of behavior problems but infertility or hypogonadism. Interviews and additional information revealed, almost without exception, the characteristic personality traits of XXY patients. At school, problems arose early, particularly in relation to language. Routine administrative acts such as 15 class repetitions had predominantly negative effects, thus increasing the patients' tendency towards social isolation. In manually oriented professions the patients were quite successful, but in apprenticeship several had to drop out due to problems in theoretical courses, especially foreign languages and mathematics. The diagnosis could nearly always have been suspected by pediatricians, school doctors or school psychologists when the patients were aged 4-8. Early diagnosis is crucial for counselling of parents and teachers, for vocational guidance and for timely testosterone replacement therapy. Patients, and their parents, could thus be spared much unnecessary suffering.