Journal Logo

You can read the full text of this article if you:

Access through Ovid
00019616-200901000-00001Miscellaneous-ArticleThe EndocrinologistThe Endocrinologist© 2009 Lippincott Williams & Wilkins, Inc.19January 2009 p 1-4Harry F. Klinefelter1912–1990Historical NoteLoriaux, D Lynn MD, PhDFrom the Department of Internal Medicine, Oregon Health and Sciences University, Portland, OR.Reprints: D. Lynn Loriaux, MD, PhD, Department of Internal Medicine, Oregon Health and Sciences University, L-607, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201. E-mail: [email protected] Klinefelter was born in Baltimore, Maryland on March 20, 1912. He did his undergraduate work at the University of Virginia and went to medical school at Johns Hopkins. He remained at Hopkins as an intern and resident in internal medicine. He next spent a year as a “traveling fellow” with Fuller Albright at the Massachusetts General Hospital. Klinefelter describes this year below:“I first worked under Dr. Howard Means, measuring oxygen consumption of adrenal gland slices in the Warburg apparatus, but I was so unsuccessful at it, breaking most of the apparatus, that in September, I asked Dr. Means if I might work with Dr. Fuller Albright, since I primarily wanted to learn some clinical endocrinology. Dr. Albright was the most outstanding clinical endocrinologist in the world, and Dr. Means readily agreed.“Albright's Saturday morning clinics were famous throughout the Massachusetts General Hospital. At the first one I attended, I saw a tall black boy named George Bland who had gynecomastia and very small testes (1.0–1.5 cm in length). When I asked Dr. Albright what this was all about, he said he did not know but that he would be happy for me to work on it. During the rest of the year, we found 8 other patients with this same condition and reported the series at the endocrine meetings in 1942. Dr. Albright was charitable enough to let me put my name first on the paper that was published later in 1942 in the Journal of Clinical Endocrinology.1 The title, “A Syndrome Characterized by Gynecomastia, Aspermatogenesis without Aleydigism, and Increased Excretion of Follicle-Stimulating Hormone,” was so long that the syndrome came to be known by my name, though it was really just another of Dr. Albright's diseases. Albright had more ideas in a day than most people have in a lifetime, and it was a great pleasure and privilege to work with him. Not only did he have great ideas and theories, but if someone came up with a fact that blasted his current theory, he soon had another one!“Figure 1 shows 6 of the original 9 patients. These patients tend to be tall, with normal secondary sex characteristics; most have normal sexual function. Figure 2 emphasizes that these patients often have an entirely normal appearance save for their small testes, and I am sure many escape detection because the testes are often not examined in a general physical examination. Figure 3 illustrates the gynecomastia of several of this group. Figure 4, a photomicrograph from a testicular biopsy, shows the atrophy and hyalinization of the seminiferous tubules with preservation of the Leydig or interstitial cells.JOURNAL/endst/04.03/00019616-200901000-00001/figure1-1/v/2021-02-17T201901Z/r/image-tiff Six of the original 9 patients with Klinefelter's syndrome. The bodies are masculine and had relatively normal development of accessory sex organs, except for breasts.JOURNAL/endst/04.03/00019616-200901000-00001/figure2-1/v/2021-02-17T201901Z/r/image-tiff XXY patient with normal androgen function.JOURNAL/endst/04.03/00019616-200901000-00001/figure3-1/v/2021-02-17T201901Z/r/image-tiff Bilateral gynecomastia in 3 of the patients that are shown in Fig. 1.JOURNAL/endst/04.03/00019616-200901000-00001/figure4-1/v/2021-02-17T201901Z/r/image-tiff Testicular biopsy. a indicates Leydig cells; b, completely hyalinized tubules; c, partially hyalinized tubules. Leydig cells (a) almost suggest adenoma formation (hematoxylin and eosin, ×200).“A few years after the syndrome was described, Heller and Nelson2 reported that the gynecomastia was not a necessary part of the syndrome, though it occurred in about 75% of the patients. The hallmarks of the syndrome, therefore, are small testes, sterility, and increased excretion of follicle-stimulating hormone.“We thought that this syndrome, which occurs in about one in 500–1,000 male births, indicated there was a second testicular hormone, analogous to estrogen in the female. Figure 5 shows diagrammatically the hormone relationships we thought existed. The solid and cross-hatched lines indicate presence of hormones; broken lines indicate absence. Stimulating influences are indicated by solid arrows, and inhibiting influences by open arrows.JOURNAL/endst/04.03/00019616-200901000-00001/figure5-1/v/2021-02-17T201901Z/r/image-tiff Top, Schematic drawing of hormonal patterns in normal female (A) and female after gonadectomy. Bottom, hormonal patterns in normal male (A), male after gonadectomy (B), and male with Klinefelter's syndrome (C).“There is a good deal of evidence from both animal and human studies to show that a second testicular hormone exists. In the male castrate, testosterone does not control hot flashes, whereas estrogen does. In this syndrome, estrogen decreases the urinary FSH excretion much more readily than testosterone. In animals, testosterone fails to correct all the hypophyseal changes after castration. This second testicular hormone has been labeled inhibin. Despite a great deal of work, it has never been isolated, but we know that it is not a steroid.“We thought the gynecomastia was caused by the action of testosterone on the breast in the absence of this second testicular hormone. Figure 6 is a photomicrograph showing the difference in the appearance of the gynecomastia in this syndrome from estrogen-induced gynecomastia, shown on the right. In the later there is more glandular tissue, and in the former, more peri-acinar fibrous tissue.JOURNAL/endst/04.03/00019616-200901000-00001/figure6-1/v/2021-02-17T201901Z/r/image-tiff Left, Breast tissue in a patient with Klinefelter's syndrome with only moderate ductal hyperplasia (a) with marked proliferation of the periductal connective tissue (b). Right, Breast tissue in estrogen-induced gynecomastia; ductal hyperplasia (a) is more marked, and periductal connective tissue (b) is less dense.“Fourteen years after the original description of the syndrome, 2 groups independently discovered that the buccal mucosal cells of these patients contained an extra chromatin mass (Fig. 7), or were chromatin positive.3,4 A few years later, Jacobs and Strong5 found that these chromatin-positive patients had 47 chromosomes, with an extra X chromosome, and were XXY. The extra X chromosome results from either meiotic nondisjunction, in which a chromosome pair fails to separate during meiosis, or from anaphase lag. Anaphase lag might result in a gamete losing a sex chromosome; a chromosome lags and is not incorporated in the new cell in the next stage of mitosis (anaphase). Such anaphase lag could account for the largest minority of karyotypes, the mosaics XY/XXY and XX/XXY. Eighty percent of these patients have positive sex chromatin, and their karyotypes may vary widely, and with many mosaics.JOURNAL/endst/04.03/00019616-200901000-00001/figure7-1/v/2021-02-17T201901Z/r/image-tiff Photomicrograph of a female cell is on the left, showing sex chromatin just under the nuclear membrane. The male cell is on the right, showing absence of this chromatin mass (×2000).“The syndrome in patients with positive chromatin in the buccal mucosa should probably be called Klinefelter's disease. Although these patients have positive female sex chromatin, they are phenotypic males and should never be considered otherwise. The other 20%, whose testes are not small, have XY chromosomes and should be studied further to determine etiology. These patients often have no complaints, and the condition is discovered in the course of a general physical examination. Sterility and gynecomastia are the most common complaints. It thought that 5% to 10% of sterile males have this condition. When this disorder is suspected, a buccal smear is the first test to request. If the cells are chromatin positive, the diagnosis is made; testicular biopsy and karyotyping are not necessary. If the buccal mucosa is chromatin negative, further studies are indicated.“The extra X chromosome in these men has stimulated much interest, but its function, if any, has not been determined. Systemic lupus erythematosus, a disorder more common in female patients, has been frequently reported in this syndrome, but the association is not statistically significant. The association with leukemia may also be coincidental. Leg ulcers, osteoporosis, and taurodontism occur with greater frequency in these patients than in control subjects, and dermatoglyphic studies have shown characteristic abnormalities.”Following his year with Fuller Albright, Klinefelter served in the US Army for 3 years during WWII. Discharged at the war's end, Klinefelter returned to Johns Hopkins and developed an interest in rheumatology, which ultimately he practiced as a member of the Johns Hopkins faculty and in private practice. He rose to the rank of associate professor of medicine in 1966. He retired from practice at 76 years of age, and died in 1990.The syndrome that Klinefelter described remains one of the commonest causes of primary male infertility, and one of the most under diagnosed of the common syndromes of abnormal sexual differentiation.JOURNAL/endst/04.03/00019616-200901000-00001/figure8-1/v/2021-02-17T201901Z/r/image-tiffHarry F. Klinefelter.REFERENCES1. Klinefelter HF, Reifenstein EC, Albright F. Syndrome characterized by gynecomastia, aspermatogenesis with aleydigism, and increased excretion of follicle-stimulating hormone. J Clin Endocrinol. 1942;2:615–627.[Context Link][CrossRef]2. Heller CG, Nelson WO. Hyalinization of the seminiferous tubules associated with normal or failing Leydig-cell function, discussion of relationship to cunuchoidism, gynecomastia, elevated gonadotropin, depressed 17-ketosteroids and estrogens. J Clin Endocrinol. 1945;5:1–12.[Context Link][CrossRef]3. Bradbury JT, Bunge RG, Boccabella RA. Chromatin test in Klinefelter's syndrome. J Clin Endocrinol. 1956;6:689.[Context Link][CrossRef][Medline Link]4. Reis P, Johnson SG, Mosbeck J. Letter to the Editor. Lancet. 1956;1:962.[Context Link]5. Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex –determining mechanism. Nature. 1959;183:302–303.[Context Link][CrossRef][Medline Link]6. Klinefelter HF. Klinefelter's syndrome: historical background and development. Southern Med J. 1986;79:1089–1903.[Full Text][CrossRef][Medline Link]00019616-200901000-0000100004678_1942_2_615_klinefelter_aspermatogenesis_|00019616-200901000-00001#xpointer(id(citation_FROM_JRF_ID_d7e257_citationRF_FLOATING))|11065213||ovftdb|SL000046781942261511065213citation_FROM_JRF_ID_d7e257_citationRF_FLOATING[CrossRef]10.1210%2Fjcem-2-11-61500019616-200901000-0000100004678_1945_5_1_heller_hyalinization_|00019616-200901000-00001#xpointer(id(citation_FROM_JRF_ID_d7e292_citationRF_FLOATING))|11065213||ovftdb|SL0000467819455111065213citation_FROM_JRF_ID_d7e292_citationRF_FLOATING[CrossRef]10.1210%2Fjcem-5-1-100019616-200901000-0000100004678_1956_16_689_bradbury_klinefelter_|00019616-200901000-00001#xpointer(id(citation_FROM_JRF_ID_d7e322_citationRF_FLOATING))|11065213||ovftdb|SL0000467819561668911065213citation_FROM_JRF_ID_d7e322_citationRF_FLOATING[CrossRef]10.1210%2Fjcem-16-5-68900019616-200901000-0000100004678_1956_16_689_bradbury_klinefelter_|00019616-200901000-00001#xpointer(id(citation_FROM_JRF_ID_d7e322_citationRF_FLOATING))|11065405||ovftdb|SL0000467819561668911065405citation_FROM_JRF_ID_d7e322_citationRF_FLOATING[Medline Link]1331946300019616-200901000-0000100006056_1959_183_302_jacobs_intersexuality_|00019616-200901000-00001#xpointer(id(citation_FROM_JRF_ID_d7e393_citationRF_FLOATING))|11065213||ovftdb|SL00006056195918330211065213citation_FROM_JRF_ID_d7e393_citationRF_FLOATING[CrossRef]10.1038%2F183302a000019616-200901000-0000100006056_1959_183_302_jacobs_intersexuality_|00019616-200901000-00001#xpointer(id(citation_FROM_JRF_ID_d7e393_citationRF_FLOATING))|11065405||ovftdb|SL00006056195918330211065405citation_FROM_JRF_ID_d7e393_citationRF_FLOATING[Medline Link]1363269700019616-200901000-0000100007611_1986_79_1089_klinefelter_klinefelter_|00019616-200901000-00001#xpointer(id(citation_FROM_JRF_ID_d7e423_citationRF_FLOATING))|11065404||ovftdb|SL00007611198679108911065404citation_FROM_JRF_ID_d7e423_citationRF_FLOATING[Full Text]00007611-198609000-0001200019616-200901000-0000100007611_1986_79_1089_klinefelter_klinefelter_|00019616-200901000-00001#xpointer(id(citation_FROM_JRF_ID_d7e423_citationRF_FLOATING))|11065213||ovftdb|SL00007611198679108911065213citation_FROM_JRF_ID_d7e423_citationRF_FLOATING[CrossRef]10.1097%2F00007611-198609000-0001200019616-200901000-0000100007611_1986_79_1089_klinefelter_klinefelter_|00019616-200901000-00001#xpointer(id(citation_FROM_JRF_ID_d7e423_citationRF_FLOATING))|11065405||ovftdb|SL00007611198679108911065405citation_FROM_JRF_ID_d7e423_citationRF_FLOATING[Medline Link]3529433 Six of the original 9 patients with Klinefelter's syndrome. The bodies are masculine and had relatively normal development of accessory sex organs, except for breasts. XXY patient with normal androgen function. Bilateral gynecomastia in 3 of the patients that are shown in Fig. 1. Testicular biopsy. a indicates Leydig cells; b, completely hyalinized tubules; c, partially hyalinized tubules. Leydig cells (a) almost suggest adenoma formation (hematoxylin and eosin, ×200). Top, Schematic drawing of hormonal patterns in normal female (A) and female after gonadectomy. Bottom, hormonal patterns in normal male (A), male after gonadectomy (B), and male with Klinefelter's syndrome (C). Left, Breast tissue in a patient with Klinefelter's syndrome with only moderate ductal hyperplasia (a) with marked proliferation of the periductal connective tissue (b). Right, Breast tissue in estrogen-induced gynecomastia; ductal hyperplasia (a) is more marked, and periductal connective tissue (b) is less dense. Photomicrograph of a female cell is on the left, showing sex chromatin just under the nuclear membrane. The male cell is on the right, showing absence of this chromatin mass (×2000).Harry F. Klinefelter.Harry F. Klinefelter: 1912–1990Loriaux D Lynn MD PhDHistorical NoteHistorical Note119p 1-4