Klinefelter syndrome with long-arm X-chromosome deletion

Klinefelter syndrome (KS)was first described in 1942 byHarry F. Klinefelter in nine men with testicular abnormalities, failure to produce spermatozoa and gynaecomastia [1], being the first sexual chromosome abnormality to be described. In 1959, Jacobs and Strong found that this phenotypewas due to the presence of an extra X chromosome [2]. Klinefelter syndrome (KS) is an ananeuploidy that affects sexual chromosomes characterized by the presence of two X chromosomes and a Y chromosome in subjects with a male phenotype. It is themost common sexual chromosome abnormality,with an incidenceof 1 in 600malebirths, being themost frequent cause of genetic infertility inmales,with a frequency of 4% [3]. Clinically, patients are tall, with narrow shoulders,wide hips,weakmuscles, scarce bodyhair, small testes, gynaecomastia and infertility. Complementary tests revealed aspermatogenesis, reduced levels of serum testosterone, elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and androgen deficiency (hypergonadotropic hypogonadism). It is associated with other comorbidities, including osteoporosis, varicose veins, thromboembolic disease, diabetes, chronic bronchitis, bronchiectasis, emphysema and neoplastic diseases. Phenotypic traits are subtle and generally remain unnoticed during childhood and adolescence. Diagnosis is usually established during puberty due to poor development of secondary sexual characters, or even in adulthood, upon investigation of infertility. We report the case of a 26-year-old man referred to the Unit of Urology due to the presence of phimosis. Reported pubarche occurred at 12 years, with deepening of voice and growth of facial hair at 18, although it is sparse and needs shaving only once weekly. He experiences erections and sexual desire, and does not show other symptoms. On physical examination, the patient has a height of 177 cm, a weight of 76.6 kg and an arm span of 180 cm, with mild phimosis, hypotrophic testes and mild gynaecomastia. Seminogram reveals a volume of sperm of 3.2 mL, translucent, with total liquefaction at 1 h and normal viscosity, with a pH of 8.5 azoospermia. Scrotal ultrasound demonstrates a reduction of the size of the testes, diffuse hypogenicity and a hyperechogenic point related to microcalcifications, without intraparenchymal lesions. Epididymes with preserved morphology, with an 8-mm cyst in the head of the left epididymis. Hydrocele or varicocele not noted. Findings related to the hormonal profile of the patient are shown in Table 1.

secondary sexual characters, or even in adulthood, upon investigation of infertility.
We report the case of a 26-year-old man referred to the Unit of Urology due to the presence of phimosis. Reported pubarche occurred at 12 years, with deepening of voice and growth of facial hair at 18, although it is sparse and needs shaving only once weekly. He experiences erections and sexual desire, and does not show other symptoms.
On physical examination, the patient has a height of 177 cm, a weight of 76.6 kg and an arm span of 180 cm, with mild phimosis, hypotrophic testes and mild gynaecomastia.
Seminogram reveals a volume of sperm of 3.2 mL, translucent, with total liquefaction at 1 h and normal viscosity, with a pH of 8.5 azoospermia.
Scrotal ultrasound demonstrates a reduction of the size of the testes, diffuse hypogenicity and a hyperechogenic point related to microcalcifications, without intraparenchymal lesions. Epididymes with preserved morphology, with an 8-mm cyst in the head of the left epididymis. Hydrocele or varicocele not noted.
Findings related to the hormonal profile of the patient are shown in Table 1. Upon diagnosis of primary hypergonadotropic hypogonadism (reduced testosterone with elevated LH and FSH concentrations), the patient was referred to the Genetic Counseling Unit. Cytogenetic test revealed the presence of 47 chromosomes in all metaphases, with an XXY chromosome and subcentromeric long-arm X-chromosome deletion. Comparative genomic hybridisation (CGH array) was performed with a male control (Promega) on the KaryoArray ® v3.0 system (Agilent), with a mean resolution of 1 oligo every 9 kb in the regions of greatest interest (detection of >25 kb gains or losses) and of 175 kb in the rest of the regions (detection of >400 kb losses or gains). The result is a genomic pattern corresponding to male sex and an arr [hg19] Xp22.33 q13.3 (60,679-74,057,587)×2 formula. Two copies were found of an approximate interval of 74 Mb located at X-chromosome region p.22.33-q13.3, being the total number of copies in males 1. Genetic findings explain the phenotype of the patient.
Follow-up is performed by the Unit of Endocrinology, where androgen replacement therapy is prescribed.
Almost 80% of patients with KS have a 47,XXY karyotype, Of them, 50% receive the extra X chromosome from their father, whereas the other 50% received it through maternal inheritance. When inherited from the mother, the error occurs during meiosis I o II or in the first mitotic division of embryonic development. Conversely, in aberrations inherited from the father, the error always occurs during meiosis. The remaining 20% of patients have other abnormalities in the number of copies of sexual chromosomes (48,XXXY; 48,XXYY; 49,XXXXY), 46,XY/47XXY mosaicisms or structural abnormalities in the X chromosome [4].
There are few case reports of KS patients with abnormalities in one of the X chromosomes. Frühmesser et al. [5] found five cases in the literature with deletions in one of the X chromosomes. In 2015, Liang et al. [6] reported the case of a 24-year-old male with infertility as initial symptom whose genetic tests revealed a KS-related aneuploidy due to an extra X chromosome of maternal inheritance. The phenotypic characteristics and genotypes of patients reported in the literature and of the case reported in this study are summarized in Table 2.
Research funding: None declared. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.