A rare case report: atypical presentation of Klinefelter syndrome in a 24-year-old male at suburban tertiary care hospital in Nepal

Abstract

Klinefelter syndrome (KS) is the most common chromosomal condition affecting males, usually caused by the presence of an extra X chromosome (47, XXY). However, it often remains undiagnosed until adulthood. We report a unique case of a 24-year-old man whose primary concern was persistent nausea and vomiting, an atypical presenting complaint of Klinefelter syndrome. Further evaluation revealed typical features of KS, including infertility despite normal sexual desire, gradual enlargement of the breasts, tall stature, sparse facial and body hair, small testes, and learning difficulties. An uncommon finding in the patient was premature loss of dentition. Hormonal tests showed low testosterone levels with elevated gonadotropins and estradiol, consistent with primary hypogonadism, and karyotype analysis confirmed the diagnosis. This case highlights the wide spectrum of clinical features associated with Klinefelter syndrome, including both typical and atypical manifestations. This report emphasizes the need for increased awareness of such unusual presentations, for early diagnosis, and a multidisciplinary approach to management that can improve physical health, psychological well-being, and overall quality of life.

Introduction

Klinefelter syndrome (KS) is the most common sex-chromosome disorder affecting males, occurring in about 1 in 660 male births. It results from sex chromosome aneuploidy, most commonly a 47,XXY karyotype, which occurs due to meiotic or mitotic nondisjunction^[1,2^].

About 90% of cases present with classic 47,XXY, and the remaining cases include mosaic forms (46,XY/47,XXY), higher-grade aneuploidies (48,XXXY; 49,XXXXY), or structurally abnormal X chromosomes[3]. It was first described in the 1940s, and it has been a topic of interest and research because of its broad clinical spectrum, including characteristic physical features, cognitive and developmental delays, and impaired spermatogenesis leading to azoospermia[3]. Despite its prevalence, nearly two-thirds of affected individuals remain undiagnosed until adulthood, when infertility is the indication for evaluation. Delayed diagnosis is commonly due to the variable presentation and limited awareness of associated clinical features, resulting in increased risks for significant medical comorbidities[2]. Early diagnosis is essential to guide management and improve long-term outcomes. The approach to management depends on the severity and range of clinical features, as well as the time of presentation[3].

HIGHLIGHTS

• Presentation of a rare case of Klinefelter syndrome

• Classic and atypical manifestations of Klinefelter syndrome

• Serum, semen analysis, and karyotyping in Klinefelter syndrome

• Early diagnosis and a multidisciplinary approach to the syndrome.

We report the case of a 24-year-old man, unable to father a child despite a normal sexual drive and exhibiting changing body morphology, who was diagnosed with Klinefelter syndrome.

Case presentation

A 24-year-old gentleman presented to our institution with complaints of severe daily nausea associated with intermittent episodes of non-projectile vomiting, for which he consumed up to 50 Halls tablets per day to suppress the nausea. He also gave a history of loosening and loss of all teeth except the left lower molar (as shown in Fig. 1) within the 2 years prior to presentation. On further enquiry, the patient reported bilateral breast enlargement that began 10 years earlier, accompanied by pain; however, there was no history of nipple discharge. His family noted that he had had bilaterally small testes since birth. The patient’s family was concerned that he was unusually tall, did not have a beard or mustache like his peers, had a change in the quality of his voice, and exhibited decreased intellectual ability. The patient was aware of his changing body morphology, had dropped out of school, and was socially isolated. The most concerning aspect for the patient himself was his inability to father a child despite a normal sexual drive. He mentioned that he was reluctant to express his symptoms because of social stigma and sought medical advice only after persistent nausea.

Figure 1.

Clinical photograph showing loss of maxillary teeth. The patient has a history of loosening and loss of the entire dentition, except for the left mandibular molar.

On physical examination, the patient was 71.5 inches tall and weighed 206 pounds, with a body mass index of 28.3. His arm span was 70.87 inches; sitting height was 52.95 inches; biacromial width (shoulder width) was 17.72 inches; bi-iliac width (hip breadth) was 18.50 inches; hip circumference was 41.57 inches; and head circumference was 22.05 inches. Vital signs were within normal limits, and he was alert, oriented, and in no acute distress. He did not have any facial abnormalities. Heart rate was regular without any rubs, gallops, or murmurs. On examination, the breasts were bilaterally enlarged and tender to palpation, with no nipple discharge, as shown in Figure 2. Sparse axillary and pubic hair, along with a sparse beard and mustache, were noted. Bilaterally reduced testicular volume was also observed.

Figure 2.

Photograph of a 24-year-old with Klinefelter syndrome showing typical features of Klinefelter syndrome: gynecomastia, tall stature, sparse body hair, no beard or mustache.

The CNS examination was normal. Mood and affect were appropriate, but the patient demonstrated mild difficulty in answering our questions and conversing with us.

Laboratory investigation, as shown in Table 1, revealed azoospermia, with no spermatozoa on semen analysis. The sample had a liquefaction time of 60 minutes and alkaline pH. It was collected at 10:45 and showed 2–3 white blood cells and 0–1 round cell per high-power field. Viscosity was normal, and the appearance was homogeneous with a gray-opalescent color. Furthermore, decreased serum testosterone levels, markedly elevated follicle-stimulating hormone (FSH), elevated luteinizing hormone (LH), mildly elevated prolactin, elevated estradiol, and low sex hormone–binding globulin (SHBG) were observed (Table 1).

Table 1.

Semen analysis and hormonal profile of the patient.

Investigations	Reports	Normal Range
Semen analysis	No spermatozoa seen Liquefaction time: 60 Ph: Alkaline Collection time: 10:45 WBC: 2–3 Round cells :0–1 Viscosity: normal Appearance: Homogenous, grey opalescent
Testosterone	100 ng/dL	300–1000 ng/dL
Follicle stimulating hormone (FSH)	24.21 IU/L	1.5–12 IU/L
Luteinizing Hormone (LH)	13.65 IU/L	1.7–8.6 IU/L
Prolactin	21.27 ng/mL	10–40 ng/mL
Estradiol	150 pg/mL	10–40 pg/mL
Sex hormone binding globulin (SHBG)	60 nmol/L	10–57 nmol/L

Based on the history, physical examination, and laboratory investigations, the patient was referred for karyotype analysis. The karyotype then confirmed the diagnosis of Klinefelter syndrome by demonstrating an XXY karyotype.

He then received intramuscular injections of testosterone (250 mg/mL) monthly for 4 months, after which his serum testosterone level improved to 350 ng/dL, as assessed in a blood sample one month later. During subsequent follow-up visits, his serum testosterone level remained within the normal range. Although his voice remained unchanged, he was able to father a child and now has a 6-month-old daughter. He was subsequently lost to follow-up.

Discussion

Klinefelter syndrome is a sex chromosome aneuploidy characterized by the presence of one or more extra X chromosomes in a phenotypic male, most commonly 47,XXY. It results from meiotic or mitotic nondisjunction, or mosaicism. It is a common genetic disorder, with most cases presenting with a 47,XXY karyotype (classical KS), while the remaining cases are either mosaic forms (47,XXY/46,XY), involve a structurally abnormal X chromosome, or consist of higher-grade aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY)^[1,2^]. Unlike most autosomal trisomies, where extra chromosomes are more frequently transmitted maternally, the extra X chromosome is inherited from either the mother or father in equal proportion[4]. While maternally derived KS can result from faults in either meiosis I or meiosis II, with meiosis II errors being more common, paternal nondisjunction occurs predominantly during meiosis I[4].

Klinefelter syndrome is characterized by small, firm testes, tall stature, long limbs, a low upper-to-lower body ratio, a small phallus, increased fat content, sexual dysfunction, low IQ, and behavioral difficulties. Extra X chromosomes lead to testicular hyalinization, fibrosis, testicular hypofunction, and decreased testosterone production, leading to sexual abnormalities like as hypogonadism, infertility, delayed puberty, gynecomastia, reduced bone density and muscle mass, sparse body hair, and reduced male secondary sex characteristics^[2,5^]. The condition results in an additional copy of the SHOX gene in the pseudoautosomal region of the X chromosome, which is responsible for the increased lower-to-upper segment ratio, long limbs, and tall stature^[5,6^]. Increased conversion of testosterone to estradiol via aromatization, associated with elevated serum LH, causes reduced testosterone and a relative increase in the estrogen-to-androgen ratio, which leads to delayed epiphyseal closure resulting in long legs with tall stature and to gynecomastia, respectively[5].

Likewise, in this case, the patient had gynecomastia, small testes, tall stature, an inability to father a child despite a normal sexual drive, an absence of a beard or mustache, and a change in the quality of the voice. These clinical features are most likely due to testosterone deficiency and elevated estrogen and LH, a pattern consistent with the laboratory findings mentioned earlier. During puberty, the characteristics of the voice are highly influenced by sex hormones. The vocal cords and associated apparatus are influenced via hormonal receptors present in them. The bulk of the laryngeal muscles and ligaments in males is increased by elevated levels of testosterone and dihydrotestosterone[7]. In our case, the deficiency of testosterone is likely the cause of the change in the quality of the voice. Patients with KS have impaired neurocognitive function, especially affecting verbal skills. Spatial and visual skills are normal in these patients. According to one study, there is a significant reduction in left temporal lobe gray matter, but this has been disputed by other studies. These patients are at risk of developing psychiatric disorders such as schizophrenia, other psychotic disorders, depression, anxiety, and ADHD[1]. Notably, our patient demonstrated decreased intellectual ability, which may be related to these underlying neurocognitive and neuroanatomical changes.

However, our patient presented with unusual features like nausea and intermittent vomiting, as well as loosening and loss of all teeth except the lower molars. Gastrointestinal manifestations include nausea, vomiting, abdominal pain, and diarrhea, which may alternate with constipation. These symptoms are frequently reported and tend to correlate with the severity of adrenal insufficiency. Vomiting and abdominal pain frequently serve as early warning signs of an impending adrenal crisis in these patients[8]. In our patient, however, the presentation was unusual, with persistent nausea and intermittent vomiting as the predominant symptoms, which prompted further evaluation and consideration of adrenal insufficiency despite the absence of other classic gastrointestinal features. It has been reported that increasing numbers of supernumerary X chromosomes are associated with a progressive decline in both Delta-4-androstenedione and DHEAS levels, accompanied by a corresponding rise in ACTH, suggesting a gene-dosage effect on adrenocortical steroidogenesis. The cortisol/ACTH ratio has similarly been found to decline in proportion to the number of extra X chromosomes, consistent with compensated adrenal insufficiency maintained only through sustained adrenocortical hyperstimulation[9]. Such subclinical steroidogenic impairment may remain undetected on routine biochemical testing, which may explain why the gastrointestinal symptoms in our patient preceded any overt biochemical evidence of adrenal compromise.

This state of subclinical steroidogenic impairment may remain undetected on routine biochemical testing yet carry significant clinical relevance. The gastrointestinal symptoms observed in our patient may therefore represent early manifestations of underlying adrenal compromise.

In KS, hypogonadism results in testosterone deficiency, which is the leading cause of osteoporosis in males. Testosterone is important in the critical stage of bone maturation to attain the peak bone mass at the end of puberty and to maintain it during adult life. It influences bone metabolism both directly, by acting on osteoblasts via the androgen receptor, and indirectly through aromatization to estrogen[10]. It reduces bone resorption during adult life and promotes periosteal bone formation during puberty^[11,12^]. Deficiency of testosterone is therefore a major risk factor for reduced bone density[10]. In this case, the loosening and falling of teeth are most likely a consequence of reduced bone density in the jaw resulting from testosterone deficiency.

In patients with Klinefelter syndrome, FSH, LH, and testosterone levels are normal at the start, but with age, levels of testosterone and sperm count decrease while levels of FSH and LH increase[1]. However, in this case, the patient presented to the hospital for the first time, and therefore no prior documentation was available; thus, these longitudinal changes could not be assessed.

Furthermore, these patients are more likely to develop metabolic syndrome, insulin resistance, and elevated LDL cholesterol, most likely due to low testosterone, which exacerbates insulin resistance^[1,13^]. However, our patient did not demonstrate metabolic abnormalities.

The diagnosis of KS remains challenging because affected boys often closely resemble those with a normal karyotype. As a result, the condition is recognized only in adulthood, when it presents with gynecomastia or infertility. Infertility is one of the most important concerns among patients with KS and is often the primary reason for seeking medical attention in adulthood[1]. In many cases, the diagnosis is made during infertility evaluation following semen analysis^[5,8^]. In our case, the diagnosis was similarly made in a 24-year-old man after he was unable to father a child despite having a normal sexual drive. Most cases with classic 47,XXY KS have impaired spermatogenesis resulting in azoospermia and reduced fertility[3]. In our patient, infertility was a major concern and semen analysis demonstrated azoospermia. Testosterone therapy was initiated and resulted in improvement of serum testosterone levels. However, fertility outcomes were not assessed during the follow-up. In the past, these patients were considered incapable of fathering a child. Advances in assisted reproductive techniques, such as testicular sperm extraction (TESE), microepididymal sperm aspiration, and intracytoplasmic sperm injection (ICSI), have helped achieve biological fatherhood in patients who have extremely reduced fertility[14].

By this point, a critical opportunity to treat cognitive difficulties, hypogonadism, and psychosocial issues during adolescence has often been overlooked. Postponed or delayed puberty must be promptly investigated to avoid missing a treatment opportunity[8]. The evaluation of KS begins with the assessment of hypogonadism or infertility. For the evaluation, 2 morning serum testosterone levels obtained on at least 2 occasions, along with assessment of serum LH, FSH, estradiol, sex hormone–binding globulin, inhibin B, and anti-Müllerian hormone (AMH), are used. Typically, FSH is more elevated than LH, the testosterone level is usually low, and the serum estradiol level is elevated, resulting in a persistently elevated estradiol-to-testosterone ratio, as seen in our case. Inhibin B and AMH are usually low as well^[5,15^]. Most cases of Klinefelter syndrome are misdiagnosed or underdiagnosed; therefore, diagnosis should be made via prenatal or postnatal karyotyping, or by chromosomal microarray testing[5]. In our case, the patient underwent a comprehensive evaluation, including semen analysis, hormone profiling, and karyotyping to establish the diagnosis. Karyotyping ultimately confirmed Klinefelter syndrome.

For the treatment of KS patients, a multidisciplinary approach involving specialties such as pediatrics, psychiatry, endocrinology, and urology is required. Testosterone therapy at the beginning of puberty gives the maximum benefit, and it can be given via various routes such as oral, transdermal, intramuscular, and buccal. The transdermal route provides the greatest benefit, but the intramuscular route is popular due to its ease of administration. Testosterone treatment promotes a masculine body habitus, along with overall effects such as increased libido, improved insulin sensitivity, decreased risk of osteoporosis, increased muscle mass, and healthy neurocognitive function. Speech therapy should be initiated as soon as a speech delay is noticed[1]. Those with gynecomastia are 20 to 40 times more likely to develop breast cancer than those without Klinefelter syndrome. Hence, it is more beneficial to perform a breast self-examination monthly. Gynecomastia is corrected surgically, particularly if required for esthetic or psychosocial purposes[8]. Fertility preservation and counseling are also essential components of management[5]. Patients with extremely reduced fertility will benefit from assisted reproductive techniques (ART), such as testicular sperm extraction (TESE), microepididymal sperm aspiration, and intracytoplasmic sperm injection (ICSI)[14].

Conclusion

Klinefelter syndrome is a prevalent genetic disorder but is frequently undiagnosed due to its wide variability in symptoms and subtle early presentation. Many patients are diagnosed only in adulthood during evaluation for infertility or gynecomastia which results in missed opportunities for early treatment of hypogonadism, cognitive impairments, and psychological problems. This case highlights both the atypical and typical manifestations of Klinefelter syndrome, which shows the broad spectrum of the condition. Early diagnosis through karyotyping, a multidisciplinary approach, and initiation of testosterone therapy at the onset of puberty are essential because they improve physical, metabolic, and neurocognitive outcomes, address related comorbidities, and improve the quality of life for people with Klinefelter syndrome. A multidisciplinary approach and long-term follow-up are essential.

Ethical approval

As the case report contains information from a retrospective period, we obtained an exemption from the requirement for ethical approval from the Institutional Ethics Committee.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request.

Sources of funding

None.

Author contributions

B.B.: conceptualization, writing – original draft, writing – review & editing. B.B.: conceptualization, writing – original draft, writing – review & editing. A.K.Y.: conceptualization, supervision, visualization, writing – review & editing. R.T.: conceptualization, supervision, visualization, writing – review & editing.

Conflicts of interest disclosure

There are no conflicts of interest.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Barada Bajracharya and Bhawana Bastola.

Provenance and peer review

Not commissioned; externally peer-reviewed.

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

AI/LLM disclosure

Artificial Intelligence (AI) tools (e.g., ChatGPT by OpenAI and Grammarly, an AI-based writing assistance tool) were used solely for language editing and improving the clarity of the text. The authors take full responsibility for the content, accuracy, and originality of the manuscript.