Illustration symbolizing the atypical presentation of Klinefelter syndrome with morbid obesity.

Uncommon Twist: When Klinefelter's Syndrome Presents with Obesity

Nico Varela in Health & Wellness December 2025 • 4 min read.

"Exploring a Rare Variant and Its Implications for Diagnosis and Treatment"

Klinefelter syndrome (KS) is a genetic condition primarily recognized as a cause of hypogonadism, characterized by the presence of one or more extra X chromosomes in males. The typical presentation involves small testes, reduced sperm production, gynecomastia (enlarged breast tissue), and a tall, slender stature. However, atypical presentations can occur, challenging established clinical expectations.

While most individuals with KS are noted for their height and lean body composition, instances of obesity are sporadically reported. This article delves into a unique case of a 35-year-old man diagnosed with a rare variant of Klinefelter syndrome accompanied by morbid obesity and diabetes mellitus, defying the usual phenotype.

This case highlights the importance of considering genetic testing in individuals presenting with unusual combinations of symptoms. It also underscores the need for further research to elucidate the complex relationship between chromosomal variations and phenotypic expression in Klinefelter syndrome.

Atypical Presentation: Klinefelter's with Morbid Obesity

Illustration symbolizing the atypical presentation of Klinefelter syndrome with morbid obesity.

A 35-year-old man, initially seeking help for obesity, was referred for endocrine evaluation due to hormonal abnormalities. His physical exam revealed a height of 174 cm, a weight of 135.8 kg, a waist circumference of 137 cm, and a body mass index (BMI) of 44.85 kg/m², classifying him as morbidly obese. Additional findings included gynecomastia, small testes and penis, and sparse body hair. Notably, he reported no voice changes and maintained erectile function.

Laboratory investigations revealed normal complete blood cell counts but impaired glucose tolerance. Endocrine studies showed elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) along with decreased testosterone levels. Testicular ultrasounds confirmed reduced testicular size, and sperm analysis indicated an absence of sperm.

Under suspicion of primary hypogonadism, a chromosome study was performed, leading to the diagnosis of a rare Klinefelter syndrome variant with the genotype 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2). This specific karyotype indicates:

An additional X chromosome (47,X).
A translocation involving the X chromosomes [t(X;X)(p22.3;p22.3)].
A deletion on one of the X chromosomes [del(X)(p11.23q11.2)].

The patient was started on testosterone enanthate injections and monitored as an outpatient. This case underscores that while the 47,XXY karyotype accounts for 80-90% of Klinefelter syndrome cases, around 10% involve mosaicism, and only about 1% exhibit X chromosome structural changes. Such variations can lead to a wide spectrum of clinical presentations, challenging the classical understanding of the syndrome.

Implications and Future Directions

The presented case highlights the importance of considering Klinefelter syndrome in the differential diagnosis of morbid obesity, even in the absence of typical features. The phenotypic variability associated with rare chromosomal variants underscores the need for comprehensive genetic testing in individuals with unclear presentations.

Further research is needed to understand how specific X chromosome structural changes influence the phenotype in Klinefelter syndrome. This includes investigating the impact of gene dosage, X-inactivation patterns, and other epigenetic mechanisms on metabolic and endocrine functions.

Ultimately, a better understanding of the genotype-phenotype correlations in Klinefelter syndrome will lead to more personalized and effective management strategies, improving the quality of life for affected individuals.

About this Article -

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Everything You Need To Know

How can Klinefelter syndrome present differently from the typical tall, slender physique?

Klinefelter syndrome is typically associated with a tall and slender physique due to the presence of an extra X chromosome, leading to hormonal imbalances. However, in rare instances, atypical presentations occur. Morbid obesity can manifest due to variations in the syndrome's genetic expression, creating a different phenotype than the usual lean body composition. This suggests that the impact of the extra X chromosome can vary significantly among individuals.

How was the rare Klinefelter syndrome variant with morbid obesity diagnosed in the 35-year-old man?

The diagnosis involved a combination of physical examination, hormonal assays, and genetic testing. Elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) coupled with decreased testosterone levels indicated primary hypogonadism. The definitive diagnosis was established through a chromosome study, revealing a rare Klinefelter syndrome variant, specifically 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2). This specific karyotype showed an additional X chromosome, a translocation involving the X chromosomes, and a deletion on one of the X chromosomes.

What is the significance of the 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2) karyotype in this case?

The 47,X,+t(X;X)(p22.3;p22.3)del(X)(p11.23q11.2) karyotype is significant because it is a rare variant of Klinefelter syndrome. It includes an extra X chromosome (47,X), a translocation involving the X chromosomes [t(X;X)(p22.3;p22.3)], and a deletion on one of the X chromosomes [del(X)(p11.23q11.2)]. This variation contributes to the atypical presentation of the syndrome, such as morbid obesity, which is not commonly associated with the classical 47,XXY karyotype that accounts for 80-90% of Klinefelter syndrome cases.

What are the broader implications of this Klinefelter syndrome case on diagnosis and clinical understanding?

This case underscores that Klinefelter syndrome can manifest with a wide range of clinical presentations beyond the typical tall, slender physique. It highlights the importance of considering Klinefelter syndrome in the differential diagnosis of conditions like morbid obesity, even when classic features are absent. The phenotypic variability associated with rare chromosomal variants emphasizes the need for comprehensive genetic testing in individuals with unclear symptoms. It may change diagnostic approaches, suggesting broader genetic screening in cases of unexplained obesity accompanied by hormonal abnormalities.

What treatment strategies were employed for the patient with Klinefelter syndrome and morbid obesity, and what were the expected outcomes?

The patient was started on testosterone enanthate injections to address the hypogonadism, a common hormonal imbalance in Klinefelter syndrome, and was monitored as an outpatient. While the response to this treatment wasn't detailed, testosterone replacement therapy typically aims to improve secondary sexual characteristics, increase muscle mass, and enhance overall well-being. The article doesn't mention specific interventions for the morbid obesity or diabetes mellitus, but these would likely involve lifestyle modifications such as diet and exercise, along with possible pharmacological interventions or bariatric surgery.