Can Prepubertal Cytogenetic Diagnosis Improve Fertility and Quality of Life in Klinefelter Patients? Observations from Omani Population
Authors: Achandira Udayakumar Muthappa 
Published: July 2019

Klinefelter Syndrome (KS) was first described 73 years ago. Surprisingly KS yet remains underdiagnosed in the population. Lack of awareness about symptoms and the guidelines of KS diagnosis among paediatricians and General Practitioners (GP) could be the main reason. Failing to perform a thorough physical examination, not considering or unable to get cytogenetic confirmation on suspected patients are causative factors for delayed diagnosis. Hence long standing comordities such as learning disabilities, psychosocial problems and Attention Deficit Disorder in children remain under-recognized behind an undiagnosed clinical condition. The benefits of early diagnosis at prepubertal age are much higher with the available technologies such as sperm retrieval from testes biopsy and intracytoplasmic sperm injection. This could drastically improve fertility and quality of life (QoL). As prenatal diagnosis is not promising, population screening is suggested to be the way of ensuring timely diagnosis. We reviewed KS patients in Oman presented over a decade at our tertiary care centre and compared our finding with review of literature available. We realized that lack of awareness, cultural reasons and early marriage among men is some of causes for late diagnosis. Hence we propose that prepubertal diagnosis should surely be the focus to improve fertility and QoL in KS patients. This is the first report of KS from the Omani population.

Klinefelter syndrome (KS) is a well-known sex chromosomal disorder in men, affecting 0.1–0.2% of the male population. About 80–90% of KS patients show 47,XXY and the remaining lesser percentage of them present in either mosaic (47,XXY/46,XY) forms or with additional sex chromosomes (48,XXXY,48,XXYY,49,XXXXY) or structurally abnormal X chromosome acquired through non-disjunction during maternal or paternal gametogenesis. KS results from a nondisjunction event in the father, in nearly half of the cases. The prevalence of KS is much higher even among men with infertility (azoospermia) ranging from ∼3%–13%. It remains underdiagnosed with significant number of patients being unidentified, while only a 10% of prepubertal KS being diagnosed. Moreover in adulthood it was estimated that only one fourth (25%) of affected males are diagnosed, mostly due to their investigation for infertility.

Comorbidities of this syndrome are more prominent than symptoms of hypogonadism and hence the underlying disorder remains undiagnosed while the comorbidity gets treated. KS is characterized by a genetic, whole gonadal dysfunction affecting germ cells from early fetal life. Signs may vary depending upon gonadal dysfunction and sex hormone deficiency during early life (young adults) to infertility in an adult male without any other signs of hypogonadism. During pre-pubertal years, the condition is underdiagnosed because of low androgen levels and non-production of sperms. Any mild developmental disorders or cryptorchidism should be an alerting signs. There are no symptoms that reliably indicate KS in prepubertal patients. Hence, suspected KS can be diagnosed by thorough physical examination (testosterone deficiency and testicular size) or chance observation during treatment of concomitant disease. The goal should be to achieve timely diagnosis. Isidori et al, (2008) claims ultrasound can suggest KS as early as puberty stage, before any signs are noticed on clinical examination.

Prenatal diagnosis of KS is a chance finding with no specific indication of ultrasound marker feature or serum screening marker. Hence, no effective way is currently available to screen the population prenatally, apart from cytogenetic(karyotype) analysis. Thus, it is only possible when amniocenteses are performed due to advanced maternal age and are likely to have the opportunity of ‘chance-diagnosis’. Although maternal age is a well-known risk factor for meiotic non-disjunction (especially for Down Syndrome); Bojesen et al found a 4-fold increase in the prevalence of KS cases with maternal age being greater than 40 years when compared to those below 24 years.

KS is also the most frequent genetic cause of azoospermia. A significant proportion of men with KF remain undiagnosed, probably because of the wide phenotypic variability and lack of knowledge of the symptoms among health professionals. From the data based on patient registries in Denmark, it is suspected that, only 25% of all KS patients are diagnosed in their lifetime. Therfore, awareness regarding KS is important among health care professionals and General Practitioners (GP). Careful clinical examination to rule out KS, followed by cytogenetic confirmation helps in early detection. This might enable early treatment which in turn might improve fertility and their quality of life (QoL). The incidence of KS may vary across different populations, however studies suggest a higher prevalence in Australian and Asian population. To date, there are no reports on KS published from Omani population.

Therefore, we have made an observation/assessment of age at diagnosis of KS, and the reasons for delayed presentation/diagnosis, from patients encountered at our centre, over the past decade. Based on our experience and the review of data available from other population, we hereby present our data from Omani population studied at our tertiary care centre. As prenatal diagnosis is not promising in detecting KS foetus, population screening is likely to the best option of ensuing timely diagnosis for these patients. We also suggest early diagnosis could possibly improve fertility and QoL among KS patients.