å¡ CASE REPORT å¡ Klinefelter's Syndrome Accompanied by Diabetes Mellitus and Diabetes Insipidus Kazuo Isobe, Toyoo Niwa, Mitsuru Ohkubo, Midori Ohba, Masahiko Shikano and Yukio Watanabe The first case of Klinefelter's syndrome accompanied by diabetes insipidus and diabetes mellitus is reported. A 41-year-old man admitted for hyperosmolar diabetic coma with a past history of diabetes insipidus was diagnosed as having Klinefelter's syndrome by endocrinological examination and sex chromosome analysis. In this case, glucose tolerance test was normalized half a year later and blood glucose was well controlled with diet therapy alone. (Internal Medicine 31: 917-921, 1992) Key words: hyperosmolar diabetic coma, metabolic acidosis, ketosis, desmopressin

Introduction

thumb and the testes were the size of the tip of the little finger. The public hair, hirci, and beard were very sparse. Klinefelter's syndrome is a representative disease of His level of consciousness was delirium. Neither motor hypergonadotropic hypogonadism which is characterized disturbances of the extremities nor abnormal reflex by small testis, azoospermia, and gynecomastia; the was found. The patient had been treated with trichlor patients have two or more X chromosomes and one or methiazide 2 mg/day for diabetes insipidus at the neuro more Y chromosomes. This syndrome is reported to be surgery clinic of this hospital from July 1982. Skull X-P accompanied by diabetes mellitus in 15% to 39% of and brain CT at this time showed dilation of pituitary fossa (Fig. 1). The family history was negative for diabetes Western patients and in 3.9% of Japanese, and is fre mellitus; his younger sister was suspected to be mental quently accompanied by endocrine disorders involving Laboratory results on admission are shown in Table deficient, although details were unknown. the pituitary and thyroid (1-4). Here we report the first 1. Peripheral blood picture showed leukocytosis and case of Klinefelter's syndrome accompanied by diabetes erythrocytosis, and blood biochemistry tests revealed insipidus and non-insulin-dependent diabetes mellitus. Case Report elevated sodium and an increased urea nitrogen/cre atinine ratio. Marked hyperglycemia was found, with a A 41-year-old man was admitted to the Emergency blood glucose level of 1,150mg/dl, and arterial blood Outpatient Department of Ogaki Municipal Hospital on gas analysis revealed metabolic acidosis. Plasma osmotic October 7, 1987 because of clouding of consciousness. pressure was 422.2Osm/kg. Testape urinalysis was From the mid-September, the patient had been very thirsty and had been drinking 7 to 8 bottles of carbonated negative for urinary ketones, whereas blood ketone bodies were slightly elevated and lactate was markedly water daily. In early October, he developed diarrhea elevated. Other laboratory tests on admission revealed which persisted for about 4 days. Subsequently, vomiting elevated amylase and elevated pancreatic isozyme frac developed and persisted, so that his poor caloric intake tion. However, no abdominal pain or tenderness was continued. On October 7, as his level of consciousness found, and ultrasound examination of the abdomen had begun to decrease, he visited our emergency revealed no pancreatic abnormality. With regard to Physical examination outpatient department.revealed obesity, decreased skin diabetes mellitus, markedly elevated glycohemoglobin tension, anemic conjunctiva, and no jaundice. Neither was found. Urinary C-peptide level (Table 2) was less rales nor heart murmurs were heard. The abdomen was than 6.0ng/ml, and daily output was 12/ig/day. These slightly distended and soft. The penis was the size of a findings led to the diagnosis of hyperosmolar diabetic From the Department of Internal Medicine, Ogaki Municipal Hospital, Ogaki coma and severe metabolic acidosis caused by elevation Received for publication May 8, 1991; Accepted for publication March 25, 1992 Reprint requests should be addressed to Dr. Kazuo Isobe, the Second Department of Internal Medicine, Nagoya University School of Medicine, 65, Tsuruma-cho, Showa-ku, Nagoya 466, Japan Internal

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Fig. 1. Skull X-P and brain computed tomograph reveals the enlargement of pituitary fossa. The white arrows show double floor of sella trucica. of blood lactate and ketone bodies. The administration of insulin and about more than 4,000ml/day of physi ological saline was immediately begun. During the first three days of the clinical course (Fig. 2), subcutaneous injection of insulin and infusion of physiological saline resulted in gradual decrease in blood glucose. While water balance reached over 9,000ml within about 36 hours after admission, the blood glucose level also decreased to 200mg/dl and plasma osmotic pressure to about 330 mOsm/kg. Thereafter, the infusion solution was replaced with glucose-added electrolyte solution and the fluid balance and electrolyte balance began to improve. The level of consciousness also im uTable rinaly s1. is Laboratory Results on Admission u rine p rotein (- ), glucose (+ + + ), uro bilino gen(- ), ketone b od y(- ) h em o gram and bloo d ch em istry W BC 17 .8 x 103/m m 3 RBC 6 .38 x 106/m m 3 H b H t P latelet N a C1 BU N CR E TP A LB

15.7 g/d l 54 .9% 29 .0 x 104/m m 3 166 m E q /l 3.8 m E q/l 126 m E q /1 52 .4 m g/dl 1.8 m g/dl 7.9 g /dl 4.8 g /dl

arterial b loo d gas pH 7 .233 pO 2 80 m m H g pc o 2 40.3 m m H g

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GO T G PT T . B ill A LP LD H

32 K -U 74 K -U 0.3 m g/dl 16.5 K -A -U 359 W ro -U

BS 1,150 m g/dl CPK 12 8 IU /1 am ylase 1,409 U (saliv ary : 2 % , pancreatic: 85.9% ) acetoacetate 90 ^m ol/l /3-hydro xybu tyrate 59 /m iol/1 to tal k eton e b od y 149 /zm ol/l lactate 23.0 ng/dl H bA IC : 13 .4 % , H b A l: 17.7% H C CV TC O 2 B ase excess

17 .2 m E q /l 18 .4 m E q /l - 9 .3 m E q/l

proved. The amylase level was normalized by the 3rd hospital day. Following the acute stage described above, despite the decline of blood glucose level, the urine volume increased gradually from 4,000 to 6,000ml/day, thus, the symptoms of diabetes insipidus became rather pre dominant. Total fluid intake was much less than urine volume and urine osmotic pressure was lower than plasma osmotic pressure. Therefore, a fluid deprivation test was not performed; for the differential diagnosis of diabetes insipidus, blood antidiuretic hormone (ADH) level and changes in urine osmotic pressure (Table 2) due to administration of desmopressin, an argine-vasopressin derivative, were determined. The ADH level was as low as 0.2pg/ml, and urine osmotic pressure was in creased to more than double, leading to the diagnosis of pituitary diabetes insipidus. Due to the findings of the external genitalia, sex hormone levels (Table 2) were determined. Elevated levels of LH and FSH and de creased testosterone were found. Sex chromosome analysis (Fig. 3) showed that cell karyotype was 47, Although this patient showed markedwas hyperglycemia XXY, and, accordingly, the patient diagnosed as in the acute stage, blood glucose was well-controlled having Klinefelter's syndrome. with diet therapy alone and even improved to the extent that neither insulin injection nor administration of oral drugs was required. Re-determination of the urinary C-peptide on the 34th hospital day showed that it was 22ng/ml, and daily output was 61.6/ig/day. Antibody of Langerhans islets was negative. The glucose tolerance test (GTT) (Table 3) performed six month after discharge also patient revealedwas a normal pattern.treated on an outpatient This subsequently Internal

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u ri n a ry C -p e p tid e G H LH F SH te sto stero n e u ri n a ry 1 7 -K S u rin a ry 1 7 -O H C S A D H

Endocrinological

Results

< 6 .O n g /m l 12 /xg /d a y (u rin e : 2 ,0 0 0 m l/d a y ) l .O n g /m l 3 9 m I U /m l 3 5 m I U /m l 0 .5 n g /m l 4 .8 m g /d ay 7 .1 m g /d ay < 0 .2 p g /m l

v a so p re ssin te st u ri n a ry o sm o tic

b e fo re 161

p re ssu r e se ru m o sm o tic

298

1 ho ur 34 5

2 hou r 48 1

3 h ou r 502

4 h our 506

14 h o u r 4 7 7 (m O sm /k g ) 2 8 4 (m O sm /k g )

p re ssu re p ro v o c a tiv e te sts fo r a n te ri o r p itu ita ry h o rm o n e s (se c re ta g o g u e s : in su lin , T R H , L H -R H ) b e fo re 15 m in 3 0 m in G H 0 .7 2 .0 5 .3 LH 60 14 0 18 0 F SH 49 78 91 A CT H 50 39 44 PR L 10 31 32 TSH 1 .4 5 .2 6 .6

6 0 m in 5 .9 230 96 130 38 5 .6

9 0 m in 3 .7 2 4 (1 110 78 26 4 .6

12 0 m in 1 .7 (n g /m l) 18 0 (m lU /m l) 9 5 (m l U /m l) 6 6 (p g /m l) 19 (n g /m l) 3 .9 (i/U /m l)

GH: growth hormone, LH: luteinizing hormone, FSH: follicle stimulating hormone, 17-KS: 17 ketosteroid, 17-OHCS: 17-hydroxysteroid, ADH: antidiuretic hormone, TRH: thyrotropin releasing hormone, LH-RH: LH-releasing hormone, ACTH: adreno corticotropic hormone, PRL: prolactin, TSH: thyroid stimulating hormone.

Fig. 2.

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course for the first three days after admission.

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Fig. 3.

Karyotype

of the patient

shows XXY pattern.

Table 3. Glucose Tolerance Test Performed Six Months Later of Western patients. On the other hand, Sagara et al (5) reported that, in Japan, the incidence of Klinefelter's after Discharge syndrome combined with diabetes mellitus is 3.9%, u ri nary C -pep tid e 22 .0 ng/m l 61 .6 /jg /day (u ri ne : 2 ,800 m l/day) which is much lower than that among Westerners (2-5). In the patients with Klinefelter's syndrome in the Western 75 g G T T before 0 .5 ho ur 1.0 h ou r 2 .0 hou r population, insulin-dependent diabetes mellitus (IDDM) BS 90 157 150 111 (m g/dl) is less frequent, hyperinsulemic hyperglycemia is more IR I 40 54 35 (/iU /m l) frequent, and control is relatively good. In Japan, how ever, IDDM is frequent, insulin response is often low, GTT: glucose tolerance test, BS: blood sugar, IRI: immunoreactive insulin. and many patients require antidiabetic medication. However, in the present case, blood glucose and insulin secretion were normalized except in the acute stage and basis. For about three years, good control of the diabetes diabetes mellitus was well controlled with diet therapy mellitus has been obtained with diet therapy alone, and alone. Half a year later, 75g glucose tolerance test the current treatment for the diabetes insipidus is chiefly revealed normal results. The proposed etiology of the the administration of desmopressin nasal drops. hyperosmolar diabetic coma in this case is as follows: the influences of multiple factors, including diarrhea, Discussion vomiting, and intake of a massive quantity of carbonated According to a report by Nielsen et al (3), Klinefelter's water, were superimposed on the considerable polyuria due to pre-existing diabetes insipidus, and consequent syndrome is accompanied by diabetes mellitus in 39% dehydration resulted in hyperglycemia of sudden onset. 920

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Although there was no clear evidence, marked hyper amylasemia found on aidmission suggested the pre existence of an endocrine dysfunction of the pancreas, to marked Itperhaps has alsodue been reporteddehydration. that Klinefelter's syndrome accompanied by other endocrine disorders involving the pituitary and thyroid are common (6). However, as reported by Oki et al, the combination of this syndrome with diabetes insipidus has been found in only one patient with dysfunction of the posterior pituitary due to germ cell tumor (7). It this case, we conjecture the cause of the combination; the persistent hyperexcretion of gonadotropin caused hypertrophy of the anterior pitu itary, which, in turn, caused dysfunction of the posterior Though the findings of visual fields and Apituitary. review of the literature revealed no reported caseocular fundus was normal, the skull X-P and brain CT (Fig. 1) of the ternary combination of Klinefelter's syndrome,

References Becker KL, Hoffman DL, Albert A, Underdahl LO, Mason HL. Klinefelter's syndrome. Arch Intern Med 118: 314, 1966. Forbes AP, Engel E. The high incidence of diabetes mellitus in 41 patients with gonadal dysgenesis, and their close relatives. Metabolism 5: 428, 1969. Nielsen J, Johansen K, Yde H. Frequency of diabetes mellitus in patients with Klinefelter's syndrome of different chromosome constitutions and XXY syndrome. Plasma insulin and growth hor mone level after a glucose J Clin Endocrinol 29: 1062, 1969. Nielsen J. Diabetes mellitusload. in patients with aneuploid chromosome aberrations and in their parents. Hum Genet 16: 165, 1972. Sagara M, Nakasono M, Makino I, Takebe K. Two cases of Klinefelter's syndrome associated with diabetes mellitus, and analysing the clinical features of all domestic reported cases. J Jpn Diab Soc 28: 677, 1986 (abstract in English). Hsueh WA, Hsu TH, Feldman DD. Endocrine features of Kline felter's syndrome. Medicine 57: 447, 1978. Oki S, Nakao K, Kuno S, Imura H. A case of Klinefelter's syn drome associated with hypothalamic-pituitary dysfunction caused by an intracranial germ cell tumor. Endocrinol Jpn 34: 145, 1987.

performed previously support this speculation. diabetes insipidus, andmay diabetes mellitus. Therefore, further study is necessary in order to clarify the relation ship of these three.

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Klinefelter's syndrome accompanied by diabetes mellitus and diabetes insipidus.

The first case of Klinefelter's syndrome accompanied by diabetes insipidus and diabetes mellitus is reported. A 41-year-old man admitted for hyperosmo...
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