Chinese Medical Journal 2012;125(5):937-940
A case of Klinefelter’s syndrome with type 1 diabetes mellitus

CAI Xiao-pin,  ZHAO Li,  MAO Min,  YANG Zhao-jun,  XING Xiao-yan ,  LI Guang-wei

CAI Xiao-pin (Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China)

ZHAO Li (Wuhan Tuberculosis Control Center, Wuhan, Hubei 430030, China)

MAO Min (Department of Pharmacy, Department of Pharmacy (Mao M), China-Japan Friendship Hospital, Beijing 100029, China)

YANG Zhao-jun (Department of Endocrinology, Department of Pharmacy (Mao M), China-Japan Friendship Hospital, Beijing 100029, China)

XING Xiao-yan (Department of Endocrinology, Department of Pharmacy (Mao M), China-Japan Friendship Hospital, Beijing 100029, China)

LI Guang-wei (Department of Endocrinology, Department of Pharmacy (Mao M), China-Japan Friendship Hospital, Beijing 100029, China)

Correspondence to:XING Xiao-yan,Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China (Tel: . Fax:86-10-84205493.
Klinefelter’s syndrome; type 1 diabetes mellitus; autoimmune
Klinefelter’s syndrome (KS) is the most common sex chromosome disease in men. Classical features of the syndrome include a eunuchoidal body habitus, small testes and hypergonadotrophic hypogonadism. There has been an increased risk of diabetes mellitus and autoimmune disease for KS patients. This paper reports a case of KS in association with type 1 diabetes mellitus. The patient was a 21-year-old man, who has been confirmed by absolute insulin deficiency and positive IA-2 autoantibody. The hyperinsulinemic euglycemic clamp test indicated his insulin sensitivity in normal range, and his blood glucose was controlled well by the insulin therapy.
Klinefelter’s syndrome (KS) is the most common sex chromosome disease in men. The presence of one or more extra X-chromosomes (the most prevalent karyotype being 47, XXY) is the major genetic abnormality of this syndrome. Classical features of the syndrome include a eunuchoidal body habitus, small testes and hypergonadotrophic hypogonadism. The risk of diabetes mellitus and risk of autoimmune disease in Klinefelter syndrome are increased.1 We report a 21-year-old patient with KS accompanying with type 1 diabetes mellitus.
A 21-year-old Chinese man was admitted to the China-Japan Friendship Hospital for the evaluation of diabetic ketoacidosis (DKA) in July 16, 2010. He presented with polyuria, polydipsia and weight loss for 4 months. He lost 14 kg of his body weight over the past 4 months. He developed nausea and generalized weakness as well as mild edema of lower limbs one week before admission. His fasting blood glucose (26.1 mmol/L) was markedly elevated, with ketoacidosis. The patient was diagnosed with Klinefelter’s syndrome from 47 XXY karyotype at 19 years of age due to his poor secondary sex characteristics and small testes. He took testosterone for over one year and stopped testosterone therapy 2 months before admission. The patient is the second child of the nonconsanguineous parents. His older sister was healthy, without a remarkable medical history. At his birth, his mother was 26 years old. There was no family history of diabetes and chromosomal abnormality, his mother was suffered from systemic lupus erythematosus.
On physical examination, his height was 171 cm, weight 52 kg, body mass index 19.2 kg/m2, arm span 175 cm, the length from pubis to the planta pedis was 88 cm, and length from pubis to the parietal area was 83 cm (Figure 1). He had prominent gynaecomastia, sparse hirci and pubes but no beard, as well. His testes and penis were small (Figure 2). Testicular volume of his testes were 3 and 4 ml for right and left one, respectively, and the penile length was 4.0 cm. At the time of admission, his blood pressure was 90/60 mmHg, body temperature 36.3°C, and pulse rate 110 beats/min. No abnormal finding was evident on physical examination of his thorax and abdomen. There was mild pitting edema in lower limbs.

view in a new window
Figure 1. The patient’s height was 171 cm, weight 52 kg, body mass index 19.2 kg/m2, arm span 175 cm, the length from pubis to the planta pedis was 88 cm, and length from pubis to the parietal area was 83 cm.
Figure 2. The patient’s testes and penis were small.
Results of the complete blood count and biochemical analysis are listed in Table 1. The data of peripheral blood lymphocyte subsets examined by flow cytometry are shown in Table 2.

view in a new window
Table 1. Laboratory findings on admission of the patient
Table 2. Lymphocyte subsets in the peripheral blood of the patient
The patient’s follicle stimulating hormone level elevatedto 25.9 mIU/ml (normal range: 0.7–11.4 mIU/ml), luteinizing hormone increased to 28.6 mIU/ml (normal range: 1.7–8.6 mIU/ml), and total testosterone was as low as 0.233 nmol/L (normal range: 4.56–28.2 nmol/L). These results were consistent with primary hypogonadism. IA-2 autoantibody was positive, as well as islet cell autoantibodies (ICA), insulin autoantibody (IAA) and glutamic acid decarboxylase antibody (GADA) were all negative. HLA genotype was DRB1*0911. Hyperinsulinemic euglycemic clamp test showed that the glucose metabolic rate (M value) was 9.39 mg/kg per minute (M value for healthy adults was (8.26±2.47) mg/kg per minute in China-Japan Friendship Hospital), which was performed before testosterone replacement therapy. Meal load test indicated low C-peptide response, C-peptide level of fasting, 0.5 hour, 1 hour, 2 hours after meal load being 0.34 ng/ml, 0.50 ng/ml, 0.69 ng/ml, 0.72 ng/ml, respectively.
Bone mineral density showed osteoporosis. Ophthal- mological findings were normal. Electrocardiogram was normal.
Klinefelter syndrome complicated with type 1 diabetes was diagnosed. Intensive insulin therapy for hyperglycemia was initiated. The results of insulin regimen and finger blood sugar monitoring were shown in Table 3. His blood glucose control was improved by injection of only 24 U of insulin per day after testosterone replacement therapy for primary hypogonadism given on July 28. After the achievement of blood glucose control, the repeated meal load test was done and C-peptide level of fasting, 1 hour, 2 hours after meal load being 0.44 ng/ml, 0.98 ng/ml, 0.45 ng/ml, respectively, indicative of no improving on his insulin deficiency.

view in a new window
Table 3. Insulin regimen and finger blood sugar monitoring
The present patient was diagnosed as Klinefelter syndrome from 47 XXY karyotype. He started taking testosterone two years ago, and stopped taking testosterone two months before admission. Therefore, the laborarory investigations showed hypergonadotrophic hypogonadism. It was reported that osteoporosis is often associated with KS.
His diabetes was characterized by the following: (1) The patient was at young age. (2) Typical hyperglycemia symptom, severe hyperglycemia with ketoacidosis, a low fasting C-peptide concentration and a badly decreased insulin secreting response to the meal load, suggesting his absolute insulin deficiency. (3) His lean body habitus, body mass index was 19.2 kg/m2. (4) Hyperinsulinemic euglycemic clamp test showed his insulin sensitivity being in the normal range. (5) There was positive autoimmune marker of type 1 diabetes such as IA-2. IA-2, a member of the protein tyrosine phosphatase family, is a major autoantigen in type 1 diabetes. Of all newly diagnosed type 1 diabetic patients, 70% have autoantibodies to IA-2, and these autoantibodies appear years before the development of clinical disease. (6) Susceptible HLA genotype for type 1 diabetes mellitus of DRB1*0911. (7) The patient’s mother suffered from autoimmune disease. (8) There was no family history of type 2 diabetes. (9) A daily dose of insulin of only 0.46 U/kg could make a good blood glucose control. Although KS was described as genetic syndrome sometimes associated with diabetes of specific type in ADA etiologic classfication of diabetes mellitus,2 all above points supported the diagnosis of type 1 diabetes mellitus.
An association between KS and diabetes has been reported in a number of studies. In 1969 Nielsen described an increased prevalence (39%) of a diabetic oral glucose tolerance test in 31 KS patients.3 New epidemiological studies on both mortality and morbidity of patients with Klinefelter’s syndrome in England4 and Denmark5 have shown an increased risk of dying from diabetes (with a standardized mortality rate (SMR) of 5.8% and hazard ratio ( HR) of 1.6, respectively) or being admitted to the hospital with diabetes (with HR for type 1 diabetes and type 2 diabetes being 2.21 and 3.71 respectively).
What is underlying mechanism of the development of diabetes in KS? KS is frequently believed to be associated with insulin resistance.6,7 Yesilova et al8 found a high prevalence (38.5%) of insulin resistance in Klinefelter’s syndrome patients using hyperinsulinemic euglycemic clamp. Insulin resistance plays an important role in the onset of diabetes in KS. Plasma testosterone concentration was inversely related to insulin resistance in patients with Klinefelter syndrome.9 Hypogonadism in Klinefelter’s syndrome may cause an unfavorable change in body composition, primarily through increased truncal fat and decreased muscle mass, leading to insulin resistance. Hyperinsulinemic euglycemic clamp test is the golden standard for evaluating insulin sensitivity. Hyperinsulinemic euglycemic clamp test in this patient indicated that he had no insulin resistance. Perhaps testosterone replacement therapy for a period of time resulted in his insulin sensitivity. Mechanisms rather than insulin resistance ought to operate his diabetes. The autoimmune damage to islet β cells, which is confirmed by positive IA-2 autoantibody and abnormal peripheral blood lymphocyte subsets, is speculated for his absolute insulin deficiency. The peripheral blood lymphocyte subsets of the present case showed a higher CD4/CD8 ratio and a large percentage of B1 cells (CD5+, CD19+). It is possible that this abnormality made him predisposed to type 1 diabetes.
Patients with KS have a higher susceptibility to autoimmune diseases such as systemic lupus erythematosis, rheumatoid arthritis, and Sjogren’s syndrome.10 Low testosterone and high estrogen levels in Klinefelter syndrome may predispose hypogonadal males to develop defects in T cell activity that lead to autoimmune disorders.11 There are several reports suggesting a possible relationship between autoimmunity and hypogonadism.
Bizzarro’s study12 found that patients with KS who experienced clinically active autoimmune disorders showed lower percentages and absolute values of CD3+ T cells and increased CD4+/CD8+ ratio compared with healthy men, and the testosterone replacement therapy improved all clinical and immunologic abnormalities and reduced the CD4+/CD8+ ratio.
In another study,13 the absolute numbers and percentages of CD4+, CD19+ cells and CD4+/CD8+ ratio for patients with KS were higher than those of healthy control subjects, and all decreased after 6 months treatment with testosterone. This demonstrates that the lack of testosterone in patients with KS enhances cellular and humoral immunity and that androgen replacement treatment suppresses this abnormality.
Both epidemiological and clinical studies show clear evidence of a dramatically increased risk of diabetes in KS. Men with KS present insulin resistance and so type 2 diabetes occurs more common in KS. There are a few case reports on KS accompanying type 1 diabetes mellitus.14 The present patient with KS was diagnosed as type 1 diabetes of new onset. This case illustrates that the presence of KS should be considered when early onset diabetes and hypogonadism coexist in one male, and the type 1 diabetes mellitus should be considered when hyperglycemia appears in KS. It is important to carefully classify the type of diabetes in KS, especially identifying patients who have positive autoantibodies and really have type 1 diabetes. By classification, early insulin treatment can be switched on and the complications associated with poor glycemic control may be avoided.
1.  Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med 1998; 158: 1309-1314.
2.  The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26: S5-S20.
3.  Nielsen J, Johansen K, Yde H. Frequency of diabetes mellitus in patients with Klinefelter’s syndrome of different chromosome constitutions and the XYY syndrome. Plasma insulin and growth hormone level after a glucose load. J Clin Endocrinol Metab 1969; 29: 1062-1073.
4.  Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA. Mortality in patients with Klinefelter’s syndrome in Britain: A cohort study. J Clin Endocrinol Metab 2005; 90: 6516-6522.
5.  Bojesen A, Juul S, Birkebæk NH, Gravholt CH. Morbidity in Klinefelter syndrome: A Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab 2006; 91: 1254-1260.
6.  Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Mosekilde L, and Bennett P, et al. The Metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care 2006; 29: 1591-1598.
7.  Ota K, Suehiro T, Ikeda Y, Arii K, Kumon Y, Hashimoto K, et al. Diabetes mellitus associated with Klinefelter’s syndrome: a case report and review in Japan. Intern Med 2002; 41: 842-847.
8.  Yesilova Z, Oktenli C, Sanisoglu SY, Musabak U, Cakir E, Ozata M, et al. Evaluation of insulin sensitivity in patients with Klinefelter’s syndrome: A hyperinsulinemic euglycemic clamp study. Endocrine 2005; 27: 11-15.
9.  Pei D, Sheu WH, Jeng CY, Liao WK, Fuh MM. Insulin resistance in patiants with Klinefelter’s syndrome and idiopathic gonadotropin deficiency. J Formos Med Assoc 1998; 97: 534-540.
10.  French MA, Hughes P. Systemic lupus erythematosus and Klinefelter’s syndrome. Ann Rheum Dis 1983; 42: 471-473.
11.  Ahmed SA, Penhale WJ, Talal N. Sex hormones, immune responses and autoimmune diseases. Am J Pathol 1985; 121: 531-551.
12.  Bizzarro A, Valentini G, Martino GD, Dapoute A, Bellis AD, Iacono G. Influence of testosterone therapy on clinical and immunological features of autoimmune diseases associated with Klinefelter’s syndrome. J Clin Endocrinol Metab 1987; 64: 32-36.
13.  Kocar IH, Yesilova Z, Ozata M, Turan M, Sengul A, Ozdemir I. The effect of testosterone replacement on immunological features of patients with Klinefelter syndrome. Clin Exp Immunol 2000; 121: 448-452.
14.  Pamuk B, Torun A, Kulaksizoglu M, Algan C, Ertugrul DT, Yilmaz Z, et al. 49,XXXXY syndrome with autoimmune diabetes and ocular manifestations. Med Princ Pract 2009; 18: 482-485.