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Postmortem diagnosis of "occult" Klinefelter syndrome in a patient with chronic renal disease and liver cirrhosis. (Case Reports).

Klinefelter syndrome is the most common chromosomal abnormality, with a predominantly 47, XXY karyotype and typical clinical findings of infertility, hypogonadism, reduced body hair, gynecomastia, tall stature, and increased gonadotropins and decreased testosterone levels. (1,2) In addition to this classic description, several other conditions have been described in Klinefelter syndrome: increased incidence of certain tumors such as breast cancer and mediastinal germ cell tumors, venous disease, autoimmune disorders, mild neurobehavioral deficit, diabetes mellitus, (1,2) sexual precocity, (3) and osteoporosis. (4) The fact that many patients lack the full or classic phenotype of Klinefelter syndrome may explain some of the variation in reported incidence from 1 in 400 (2) to 1 in 1000. (5) In addition, it appears that many cases of Klinefelter syndrome go undiagnosed, (2,6) with potentially serious treatment consequences. This study details the case of a patient with chronic renal disease and liver cirrhosis in whom clinical features did not suggest Klinefelter syndrome and the diagnosis was only made post mortem. Autopsy revealed hypogonadism, and Klinefelter syndrome was confirmed by fluorescent in situ hybridization (FISH) for sex chromosomes and hormone analysis of serum.


A 49-year-old Japanese man had nephrosis at the age of 25 years and had been a long-term, heavy drinker From the age of 39 years, he had been undergoing dialysis for chronic renal failure, at which time he was diagnosed as having diabetes mellitus and liver cirrhosis. At the age of 48 years, he underwent surgery for esophageal varices. A year later, he complained of nausea during an in-hospital dialysis session. The nausea persisted and, with gradual loss of consciousness, he was taken to the emergency department, where he exhibited massive hematemesis, hypotension, hyperpotassemia, and hypovolemic shock. Despite intensive resuscitation procedures, he died 8 hours after hospital admission. It was not known whether the patient was fertile when younger; he had no children during his life. He underwent autopsy within 2 hours. Cause of death was recorded as liver failure due to non-B, non-C liver cirrhosis, heavy alcohol consumption, and rupture of esophageal varices. Autopsy revealed hypogonadism, suggesting the possibility of Klinefelter syndrome, and a bilateral nodular testicular lesion. Accordingly, a hilar lymph node of the lung and the testicular lesion were investigated for chromosomal analysis by FISH, serum hormones were analyzed, and the testicular lesion was sampled for histologic evaluation by light and electron microscopy.


Tissue specimens were fixed in 15% formalin, embedded in paraffin wax, and processed according to conventional histologic techniques for subsequent sectioning and staining in hematoxylin-eosin. Samples of the nodular testicular tissue were retrieved from formalin and fixed in phosphate-buffered glutaraldehyde, then fixed in osmium tetroxide, and embedded in epoxy resin according to conventional procedures. Ultrathin sections were stained with uranyl acetate and lead citrate and examined in a JEOL 1200EXII electron microscope. FISH was applied to 50-[micro]m-thick sections of the hilar node and the nodular testicular tissue, using probes CEPX (DXZ1) and CEPY (DYZ1) (VYSIS Co, Downers Grove, Ill). Specimens and probes were denatured at 75 [degrees] C, hybridized at 37 [degrees] C overnight, washed, then stained with avidin-fluorescein isothiocyanate and rodamine-conjugated antidigoxigenin. Sections were counterstained for cell nuclei with DAPI, and for each tissue 200 nuclei were examined in an Olympus fluorescence microscope. Hormone analysis on blood sampled from the heart and frozen at -80 [degrees] C was carried out at the central clinical laboratories of Saiseikai Central Hospital and Special Reference Laboratories Inc (Tokyo, Japan).


The main autopsy findings were liver cirrhosis, end-stage kidney disease (membrano-proliferative glomerulonephritis on histologic analysis), cardiomegaly, generalized atherosclerosis, colonic polyps, and right pleurisy. The patient was 168 cm tall and weighed 75.3 kg. He showed marked hypogonadism (small penis and testes) (Figure, A) with little body hair, but no gynecomastia. Both testes were attached to an epididymis but were atrophied and contained brown tissue (Figure, B), which consisted of nodules 2 to 5 mm in diameter. Hematoxylineosin sections revealed a nodular Leydig cell hyperplasia (Figure, C). FISH stained the X and Y chromosomes orange and green, respectively. In the hilar lymph node, 40.5% (81 nuclei) showed the normal male karyotype, whereas 59.5% (119 nuclei) showed XXY. In the nodular Leydig cell hyperplasia, 86 nuclei (43.5%) were normal, 109 nuclei (54.5%) were XXY (Figure, D), and 5 nuclei (2.5%) revealed a XXXY karyotype. By electron microscopy, Leydig cells contained smooth endoplasmic reticulum cisternae in the form of vesicles and as concentric configurations, rounded mitochondria with clarified interiors, and prominent lipofuscin granules. Hormone concentrations in blood serum were as follows: luteinizing hormone, 29 MIU/mL (normal, 1.8-5.2 MIU/mL); follicle-stimulating hormone, 35 MIU/mL (normal 2.9-8.2 MIU/ mL); testosterone, 215 ng/dL (normal 250-1100 ng/dL); human chorionic gonadotropin, 1.5 MIU/mL (normal, less than 1.0 MIU/mL); and Et-human chorionic gonadotropin, 0.2 ng/mL (normal, less than 0.1 ng/mL).



The subject of this case report was a patient whose clinical condition (chronic renal disease and liver cirrhosis) and physical dimensions did not indicate Klinefelter syndrome while he was alive. He had diabetes mellitus, which is known to occur in Klinefelter syndrome, but this is only one of many pathologic findings associated with this condition. (1) It was only following death from ruptured esophageal varices that a postmortem examination revealed hypogonadism, which suggested the possibility of Klinefelter syndrome. FISH, subsequently carried out on 2 tissue samples and showing a mosaic karyotype 46XY, 47XXY, and hormonal analyses on serum confirmed the condition. These observations indicate the usefulness of postmortem investigations in demonstrating Klinefelter syndrome in those cases where the clinical features in life may not amount to a classic picture or, as in this case, where Klinefelter syndrome was not suspected, in effect, an "occult" Klinefelter syndrome patient. The postmortem determination of Klinefelter syndrome can thus help to establish a more precise incidence of this condition, given the differing incidences cited in the literature, (2,5) one aspect of which is that many cases probably go undiagnosed. (2,6) The mosaic karyotype may be regarded as consistent with a lesser degree of clinical expression of Klinefelter syndrome, as in this case.

The Leydig cell hyperplasia is commonly associated with Klinefelter syndrome and is expected because of testicular atrophy. Although it was absent in the cases studied by Klinefelter et al, (7) it has subsequently been implied as a characteristic of Klinefelter syndrome (8) and is listed as a feature of this condition in the Armed Forces Institute of Pathology fascicle. (9) The testicular pathologic findings of Klinefelter syndrome include atrophic tubules, (3) sclerosing tubules with Sertoli cell hyperplasia, (8) benign epidermal cyst, solid benign Leydig cell tumor in a patient who also had Osgood-Schlatter disease, (10) Leydig cell tumor, adenomatous Leydig cell tissue in combination with more histologically heterogeneous elements, and testicular germ cell tumor. (9) A bilateral nodular Leydig cell hyperplasia, as shown here, is a variation on the theme of Leydig cell proliferations, which appear-to be common in Klinefelter syndrome. (9)


(1.) Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med. 1998;158: 1309-1314.

(2.) Geschwind DH, Boone Kg, Miller BL, et al. Neurobehavioral phenotype of Klinefelter syndrome. Meat Retard Der Disabil Res Rev. 2000;6:107-116.

(3.) Bertelloni S, Battini R, Baroncelli GI, et al. Central precocious puberty in 48, XXYY Klinefelter syndrome variant. J Pediatr Endocrinol Metab. 1999;12:459-465.

(4.) Yamauchi M, Tadano M, Fukunaga Y, et al. Low bone mineral density in a case of mosaicism Klinefelter syndrome: rapid response to testosterone therapy. Endocrine J. 1998;45:601-604.

(5.) Connor JM, Ferguson-Smith MA. Essential Medical Genetics. 3rd ed. Oxford, England: Blackwell; 1992:135.

(6.) Hagenas L, Arver S. Klinefelter syndrome affects mostly boys: an underdiagnosed chromosome abnormality [in Swedish]. Lakartidningen. 1998;95:2686-2690.

(7.) Klinefelter HF, Reifenstein EC, Albright F. Syndrome characterized by gynecomastia, aspermatogenesis without A-Leydigism, and increased excretion of follicle-stimulating hormone. J Clin Endocrinol. 1942;2:615-627.

(8.) Rodriguez de Ledesma JM, Cozar-Olmo JM, Nistal-Martin N, et al. Klinefelter syndrome with hypogonadotropic hypogonadism and absence of Leydig cells [in Spanish]. Arch Esp Urol. 1994;47:618-620.

(9.) Ulbright T, Amin MB, Young RH. Tumor-like lesions of the testis, paratestis, and spermatic cord. In: Rosai J, Sobin LH, eds. Tumors of the Testis, Adnexa, Spermatic Cord, and Scrotum. Washington, DC: Armed Forces Institute of Pathology; 1999:291-337. Atlas of Tumor Pathology; 3rd series, fascicle 25.

(10.) Okada H, Gotoh A, Takechi Y, et al. Leydig cell tumor of the testis associated with Klinefelter's syndrome and Osgood-Schlatter disease. Br J Urol. 1994; 73:457.

Accepted for publication August 3, 2001.

From the Department of Pathology, School of Medicine, Keio University, and Saiseikai Central Hospital, Tokyo, Japan (Drs Matsuoka, Orikasa, and Yamazaki); and Christie Hospital, Manchester, England (Dr Eyden).

Reprints: Kazuto Yamazaki, MD, Department of Pathology, Saiseikai Central Hospital, 1-4-17 Mita, Minatoku, Tokyo 108-0073, Japan (e-mail:
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Author:Matsuoka, Kentaro; Orikasa, Hideki; Eyden, Brian; Yamazaki, Kazuto
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Mar 1, 2002
Previous Article:Cavernous hemangioma of spermatic cord: report of a case with immunohistochemical study. (Case Reports).
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