A discussion of anesthesiologically relevant aspects of Klinefelter syndrome -a case report-

Article information

Korean J Anesthesiol. 2025;78(1):73-78
Publication date (electronic) : 2024 November 11
doi : https://doi.org/10.4097/kja.24486
Department of Anesthesiology and Intensive Care Medicine, University Hospital of Giessen and Marburg, Campus Marburg, Marburg, Germany
Corresponding author: Christine Gaik, M.D. Department of Anesthesiology and Intensive Care Medicine, University Hospital of Giessen and Marburg, Campus Marburg, Baldingerstrasse, 35033 Marburg, Germany Tel: +49-64215865981 Fax: +49-64215865971 Email: gaikc@med.uni-marburg.de
Received 2024 July 17; Revised 2024 October 11; Accepted 2024 October 11.

Abstract

Background

Klinefelter syndrome (KS), usually the 47,XXY karyotype, is the most common sex chromosome anomaly in males. However, many cases remain undiagnosed because the clinical presentation is highly variable and physicians are not sufficiently trained to assess for this condition. To the best of our knowledge, only three detailed reports on anesthesia in patients with KS are currently available.

Case

We report the case of a 74-year-old male with KS who underwent ureterorenoscopy under general anesthesia. Despite the characteristic clinical presentation of KS and its typical sequelae, the course of anesthesia was unremarkable.

Conclusions

Despite the unremarkable anesthetic course in our case, anesthetists should be aware of the potential for a difficult airway and cardiovascular and other complications associated with this syndrome. During preoperative examination, attention should be paid to common secondary manifestations of KS to avoid perioperative complications.

Klinefelter syndrome (KS) is the most common sex chromosome aberration in males, with a prevalence of around 1-2/1000 newborn males [1]. However, many cases remain undiagnosed owing to the highly variable clinical presentation of KS and the lack of training among physicians to assess for this condition [13]. Genetically, patients with KS have at least one extra X chromosome, which can be inherited from both parents. Diagnosing KS involves karyotyping, with 47,XXY being the most common [1]. Impaired spermatogenesis, androgen deficiency, and hypogonadism are common features of this disorder. Classic clinical signs include gynecomastia, small testicles, sparse body hair, tall body size, and infertility [1,4]. Although hypogonadism is characterized by a low testosterone concentration, the pathophysiology of KS is assumed to be determined by X-linked factors and not solely by testosterone deficiency [2]. However, neurocognitive and psychosocial manifestations, as well as disorders of metabolism, bone metabolism, and the cardiovascular system can also be common concomitant diseases [1,5]. Symptoms specific to KS usually appear in adulthood, as they are often not apparent in childhood and are nonspecific in adolescence [13]. Testosterone substitution is the primary therapeutic approach for KS, supplemented by the treatment of comorbidities [6].

We present this case report of a patient with KS to highlight the relevant aspects of this common chromosomal anomaly for anesthesiologists. For the preparation and publication of this case report, we obtained written informed consent from the patient and approval from the Ethics Committee of the Philipps University of Marburg (Az.: 24-87 RS).

Case Report

A 74-year-old man presented to the emergency department in January 2024 with a 2-day history of right-sided flank, back, and upper abdominal pain.

The patient was diagnosed with KS at age 17 (karyotype XXY). None of his siblings (eight brothers and two sisters) had KS. The patient lived with his wife and had a daughter, although the patient was not the biological father (sperm donation). Since suffering a stroke in 2021, he has been bedridden and dependent on home care. Apart from high blood pressure, the patient had no known cardiovascular diseases. He also suffered from chronic pain syndrome and an essential tremor that occurred mainly on the right side and was exacerbated by emotional stress. Home medications included transdermal fentanyl, metamizole, propranolol, primidone, clonazepam, and alendronic acid.

On presentation, the patient reported colicky and cramp-like pain that was different from his chronic pain. The patient had no fever or chills and his vital signs were stable upon admission. On physical examination, the abdomen was soft, but tenderness was present in the right upper abdomen and pain was reported on percussion in the right renal bed. The left renal bed and external genitalia were unremarkable.

Sonographically, the urinary bladder showed smooth walls and the right kidney showed grade 1–2 ectasia, with a concrement reflex at the pyeloureteral junction. The left kidney was hypotrophic without ectasia or concrements. A bladder catheter was inserted and 500 ml of concentrated urine was spontaneously emptied. Urinalysis revealed mild leukocyturia and microhematuria but no evidence of nitrite. The laboratory results at admission were largely unremarkable, except for slight anemia and slightly elevated C-reactive protein levels.

After admission, a ureterorenoscopy was scheduled due to signs of right-sided ureteral colic. Preanesthetic assessment revealed a lean nutritional state (60 kg, 178 cm), with reduced general condition and affectivity. Airway examination revealed no abnormalities (Mallampati grade 1) except for a sunken face due to dentures. No complications were reported with previous anesthesia (subcutaneous mastectomy on the left side in 1983 and on the right side in 2019). The patient denied having any allergies. He had been fasting for 12 hours and denied having any reflux symptoms, nausea, or vomiting. The patient was informed about general anesthesia (GA).

On arrival at the operating room the following day, the patient’s vital signs were normal (sinus rhythm 80/min, blood pressure [BP] 130/70 mmHg, SpO2 96% on room air). After preoxygenation, the patient received 0.2 mg fentanyl and 120 mg propofol to induce anesthesia. After sufficient mask ventilation without additional aids, a laryngeal mask (SupremeTM, size 5) was inserted without any complications. No leakage was noted at a cuff pressure of 50 mmHg. The patient was ventilated under pressure control (FiO2 0.5, positive end expiratory pressure 3 cmH2O, Pinsp 15 cmH2O, respiratory rate 12/min, minute volume 4.6 L/min).

According to the standards at our clinic, anesthesia was maintained by total intravenous anesthesia (TIVA) with propofol and remifentanil (initial doses of 350 mg/h propofol and 800 μg/h remifentanil). The depth of anesthesia was controlled using the bispectral index (BIS), with a goal of 40–60. The dose of propofol was thus reduced to 250 mg/h and the dose of remifentanil to 500 μg/h. To maintain a mean arterial pressure > 65 mmHg, the patient received norepinephrine (3–6 μg/min) via a perfusor.

After repositioning from the supine to the lithotomy position, a ureterorenoscopy was performed and the double-J stent was changed by the urologists without any complications. The duration of the procedure was 30 minutes.

For postoperative analgesia, the patient received 1 g of metamizole, while for postoperative nausea and vomiting prophylaxis, 4 mg of dexamethasone and 1 mg of granisetron were administered. The patient woke up a few minutes after the TIVA completed. The laryngeal mask was then removed and the patient was found to be breathing adequately. The patient was then transferred to the recovery room on 6 L/min of oxygen. The Aldrete score on admission was 11. In the recovery room, breathing, heart rate, and BP remained stable, and the patient responded adequately. The patient reported no pain, and after 45 min he was transferred to the general ward (Aldrete score, 14). On postoperative day 1, a contralateral double ureteral stent was placed under local anesthesia by the urologists without complications, and the patient was transferred back to his home environment a few hours later.

Discussion

To the best of our knowledge, only three detailed case reports on anesthesia in patients with KS are currently available. Wei et al. [7] reported a patient who received propofol, succinylcholine, and atropine for electroconvulsive therapy. Lee et al. [8] reported a patient who showed a malignant hyperthermia (MH)-like reaction during oral surgery with sevoflurane but, like our patient, showed unremarkable recovery after TIVA. In contrast, Kato et al. [9] reported no complications after sevoflurane and fentanyl were used to maintain anesthesia. A fourth case report, conducted by Van Laeken et al. [10], describes phacoemulsification under uneventful GA in a patient with KS; however, no details regarding the type of GA were provided.

As KS is one of the most common chromosomal abnormalities in men, anesthesiologists should be aware of a few important considerations. First, up to 10% of patients with KS have osteoporosis and an increased risk of fractures [5,6,11]. This should be considered during patient positioning and airway management. Owing to the presumed increased risk of tooth decay, dental status may be compromised in patients with KS and should be considered when securing the airway [1,9]. Furthermore, malformations, such as cleft palate, occur in 18% of patients with KS [6]. Our patient had chronic pain syndrome due to osteoarthritis and osteoporosis with cervicothoracic hyperkyphosis, though airway protection was not compromised. Following thoracic sintering fractures as well as pronounced lumbar spondylarthrosis and intermittent cervicobrachial and trigeminal neuralgia on the right side (allodynia), the patient was already receiving fentanyl transdermally (75 μg/h).

KS has also been associated with several pulmonary diseases [12]. However, respiratory tract pathologies or complications among patients with KS are only sporadically reported. Barnardo et al. [13] reported a case of malignant catatonia (MC) complicated by type II respiratory failure secondary to a combination of MC and thoracic abnormalities associated with KS, which had previously been undiagnosed. Furthermore, two reports of congenital pulmonary airway malformations associated with KS are available [14,15]. Morales et al. [16] also reported significantly reduced lung compliance in patients with KS, assumed to be associated with reduced elasticity of the lung matrix. Although the exact pathomechanisms are unknown, they could be associated with testosterone deficiency. If no lung parenchymal defect is known, restrictive syndrome or decreased functional residual capacity (FRC) in KS may be caused by chest wall abnormalities (e.g., obesity, kyphoscoliosis, or pectus excavatum) [17]. Muscular weakness owing to testosterone deficiency can also promote a restrictive pattern [17]. Ladias et al. [18] reported a patient with KS whose recurrent asthma exacerbations improved with testosterone substitution, for which testosterone was described as a protective and immunosuppressive agent. KS is also associated with autoimmune diseases such as systemic lupus erythematosus [9,19]. In our patient, no respiratory diseases were diagnosed, and only low ventilation pressures were required to achieve adequate ventilation.

Additionally, increased truncal or abdominal fat can push the diaphragm cranially and may impair the FRC of a patient with KS. Therefore, adequate pre-oxygenation should be a primary focus for these patients. In addition, significantly lower maximum oxygen uptake (VO2max) has been observed in patients with KS, irrespective of testosterone substitution [20]. Pasquali et al. [21] found significantly reduced cardiopulmonary performance in patients with KS compared to healthy subjects, which was reflected in significantly reduced VO2 uptake and a lower anerobic threshold. Furthermore, fifty percent of patients with KS showed chronotropic incompetence, while none of the subjects in the control group did. Chronotropic incompetence was thus subsequently discussed as a possible factor for reduced cardiopulmonary performance and increased cardiovascular risk in patients with KS.

Echocardiographic examinations of 69 patients with KS also revealed increased intima-media thickness (IMT) in the common and internal carotid arteries [21]. Increased IMT causes a diffuse and homogeneous increase in arterial wall thickness and is considered a surrogate marker for atherosclerotic disease and a subclinical marker for early atherosclerosis. Mild diastolic dysfunction was also more frequent in patients with KS than in those in the control group [21]. In our patient, color-coded duplex sonography revealed no hemodynamically relevant stenosis in the extracranial cerebral arteries. Results regarding the frequency of valvular heart disease in patients with KS are inconsistent: some authors have reported a higher incidence among patients with KS (e.g., mitral valve prolapse and aortic valve disease), while others have not found an increased incidence of valvular heart disease in patients with KS [21,22].

However, whether the increased cardiovascular mortality (reduced life expectancy by 2–3 years) and morbidity are caused by KS alone or whether other (e.g., socioeconomic or epigenetic) factors play a role is not currently known [1,5,6,21]. Men with KS have been found to have markedly shorter QTc intervals on electrocardiogram (ECG), which may be aggravated by testosterone substitution [23]. Shortened QTc intervals may, in turn, be associated with an increased risk of arrhythmias or sudden cardiac death. Therefore, measuring the QTc interval on a 12-lead ECG at least once (and at individual risk) in patients with KS is recommended [1]. Most of these data are based on a small number of cases or case reports. Although large randomized controlled studies on the cardiac risk profile of patients with KS are lacking, anesthesiologists should consider these indications when caring for this patient population. Our patient’s ECG showed no abnormalities, with no evidence of a shortened QTc interval.

Interestingly, testosterone replacement therapy has not been shown to necessarily lead to the normalization of cardiovascular abnormalities and parameters; therefore, chromosomal abnormalities appear to play more of a role than only causing hypogonadism [20,21]. Our patient had been receiving testosterone therapy (gel) temporarily since 2006 because of increasing gynecomastia and mastodynia.

Although patients with KS are often abdominally obese [20] owing to an unfavorable muscle-fat ratio with decreased muscle mass and increased body fat, the body mass index may be in the normal range, as with our patient [6]. The extent of the increased total body fat and reduced lean body weight and muscle mass in patients with KS must be noted in terms of pharmacokinetics, although no data are currently available [20]. Preoperative clinical examination, including the estimation of muscle mass in patients with KS, could help quantify possible muscle weakness. Depending on the extent of muscle weakness, anesthesiologists should reconsider the use of neuromuscular blockers and, as in our case, avoid them if possible.

Almost half of the patients with KS have metabolic syndrome and 10%–39% have type 2 diabetes mellitus [6,20]. Therefore, the perioperative focus should be on identifying and optimizing the treatment of typical concomitant cardiovascular diseases. Our patient had also suffered a stroke two years before admission, resulting in right-sided hemiparesis. Previous data indicate that patients with KS have an increased mortality rate due to diabetes, non-ischemic heart disease, cerebrovascular disease, and some forms of neoplasia (e.g., breast and lung), among other causes [1,22,24].

KS leads to a state of hypercoagulability secondary to hyperestrogenism and hypoandrogenism, and the risk of thrombosis or pulmonary embolism is 3–6 times higher than that in the general population [1,25]. This increased risk of thromboembolism should be considered perioperatively. Likewise, anticoagulation should be considered when planning neuraxial regional anesthesia procedures as well as bleeding and coagulation management.

Because of the testosterone deficiency, mild anemia can occur [5]. Our patient had experienced intermittent anemia since 2004. However, an upper gastrointestinal endoscopy performed in 2010 showed no corresponding pathology. Because the patient only underwent low-risk surgery, no further precautionary measures were performed. In high-risk surgeries, anemia should be addressed by considering the patient’s blood management guidelines.

The literature on sex-dependent sensitivity to anesthesia is controversial. However, various models are currently being used to investigate the influence of sex hormones on neuronal signaling processes and neurotoxicity. The results suggest that testosterone plays an important role in several key signaling pathways critical for the protection of neurons and the normal function of neuronal circuits in the male mammalian brain [26,27]. The clinical relevance and extent to which these results demonstrate the influence of testosterone on sensitivity to anesthetics can currently only be speculated in patients with KS. Further studies are required to address this issue. Monitoring the depth of anesthesia (e.g. BIS) could be particularly useful for patients with KS.

Several cases of a very rare combination of KS and the simultaneous presence of dystrophinopathy (e.g. X-linked Duchenne or Becker muscular dystrophy) have also been reported [28,29]. One case report described a patient with KS who simultaneously showed symptoms of progressive muscular atrophy, which simulated X-linked Kennedy’s disease, and spinal and bulbar muscular atrophy. The assumption that this is a coincidental finding is countered by the assumption that the X-chromosome plays an important role in motor neuron biology [30]. Due to the low number and sporadic nature of reported cases, the actual association between (X-linked) muscle diseases and KS cannot currently be determined. We can also only speculate about the anesthesiologic relevance of these considerations and the extent to which trigger-free anesthesia might be beneficial for these patients. Apart from the case report by Lee et al. [8], to the best of our knowledge, no other reports of MH-like reactions are available. However, the presence of muscular dystrophy is important for anesthesiologists. Succinylcholine should be avoided in these patients because acute rhabdomyolysis, hyperkalemia, and cardiac arrest may occur [31].

KS is relatively common yet underdiagnosed. Many physicians in the perioperative setting are unaware of this syndrome and do not consider the potential anesthesiologic problems associated with KS (and its frequent comorbidities). Overall, the care of patients with KS requires a multidisciplinary approach, particularly regarding the optimization and treatment of typical concomitant diseases to reduce the perioperative complications.

Notes

Funding

None.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Data Availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Author Contributions

Christine Gaik (Writing – original draft; Writing – review & editing)

Katharina Politt (Writing – original draft; Writing – review & editing)

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