JUVENILE XANTHOMA MULTIPLEX

CASE REPORT AND DISCOS~ION OF THE LITERATURE ARTHUR B. MMRAW, M.D.

Detroit

Since Rayer, in 1835, described a patient with “plaques jauniitres des paupihes,” a great variety of lesions have been re- ported which have come to be grouped under the general descrip- tive term “xanthoma.” Of these, a well recogniged though rela- tively rare subgroup is known as “juvenile xanthoma multiplex.’’ The chief characteristic of this group is the ocourrence, before or during puberty, of multiple, scattered cutaneous nodules of typical gross appearance and characteristic microscopic structure, asso- ciated usually with good general health, occasionally with xanthom- atous lesions of other body structures, and probably always with certain underlying abnormalities of lipid metabolism. The con- dition is strikingly similar, clinically, to the more frequently ob- &wved adult variety, but like the adult form of xanthoma multi- plex, it is to be differentiated.from those forms of xanthoma which are associated with diabetes mellitus. The first of these juvenile oases of xanthoma multiples to be reported was that of Virchow, in 1871. During the sixty years that have followed, 86 authors have reported some 120 cases, if we confine ourselves to the litera- ture of Germany, France, Italy, Great Britain, and North America.

Having had the opportunity of observing the development of one such case from its inception over a period of two years, the author has felt justified in presenting the following report and discussing it in the light of the literature bearing upon the problem of xan thoma.

CASE REPORT R. 8. M., a two-and-a-half-year-old white boy of American parentage, is the

youngest of four children, born at a normal, full-term labor, and weighing at birth 9 lbs. 12 oe. There is no familial history of xanthomatous leeions either among his foreheare or in his two sisters and one brother. Five days after birth the child showed symptoms of hypertrophic (spastic) pyloric stenosis. These symptoms gradually lessened under atropine therapy and special feeding, finally disappeared, and from the age of six weeks he haa had a normal feeding, nutritional, digeative, and bowel history. His teeth erupted regularly, early and with minimal associated symptoms. No exanthemata have occurred thus far, no operations other than cir- amcision, and the child’s only severe illnees has been croup, at two and a half years. He has been unusually active, mentally and physically.

1 Accepted for publication June 1932.

19 346;

346 ABTHUR B. MO OBAW

At the age of one year, what was flrst thought to be a small pimple was notieed in the crease of the right groin. It was not more than 0.1 am. in diameter, slightly raised, pink in color, and not tender. This lesion p w gradually daring the next two months to a circular, faintly umbilicated, pinkish-yellow nodule 0.3 em. in di- ameter. In the course of another two months it had beaome oval in shape, measur- ing 0.5 x 0.4 cm. in dimensions, waa slightly more raised, non-umbilicated, and saffron yellow in aolor. During the four months following the onset of thie flrst lesion, 16 other nodules appeared at irregular intervals. They were similar in ap- pearance and development but in only one instanoe reached the size of the flrst legion. They were for the most part circular, measuring 0.2 to 0.3 cm. in diameter. Two of these lesions were close together on the penis and scrotum, three were in the upper thoracio region near the arilla, eight on the lower abdomen, and three in the left groin. The arrangement of the lesions waa suggestively but not aoneistently symmetrical. At no time except after treatment was there any evidence of itohing of the lesions or of any inflammatory reaction in the surrounding tissues.

When the child was fourteen months old, one of the lower abdominal lesions of medium s h was excised for diagnosis under looal anesthesia. The nodule was sec- tioned and a diagnosis was made of xanthoma multiplex. The details of the micro- scopic examination are given below. At the age of 5fteen months all the lesions ex- cept the two on the penis and eerotum were treated with radium. The original lesion in the right groin was treated for an hour and a half with one 3.5 mg. platinum needle flltered with 0.4 platinum and a rubber Blter, at a distance of 2 mm. The remaining 14 lesions were treated in four groups in successive weeks, with a full strength plaque, no filter, double adhesive, tfiirty minutes.

The only immediately observable reaction to this treatment was the appearance, within seven days, of a faint erythemahus areolar zone, 0.5 mn. wide, around each nodule, fading in the mume of two weeks more and leaving a zone of like size slightly paler than the untreated skin. In the course of time these pale zones re- sumed their normal aolor. For two weeks after eaoh radium treatment the child was markedly irritable and there appeared to be slight itching of the lesions, but not enough to lead to any trauma either by scratching or rubbing.

During the subsequent six months no observable change took place in any of the lesions, save that on the scrotum. This untreated nodule disappeared spontaneously without leaving a trace. Due to the apparent non-activity of the radium, carbon dioxide snow was applied to one of the larger abdominal lesions without appreoiable effect. In the meantime a considerable number of new lesions had appeared, some on the abdomen, one or two back of the knees, several on the back, all but two of them small in size.

In the course of three more. months, however, i.s., nine months after the applica- tion of radium, regressive changes began to ocour in all but four of the treated le- sions. These changes consisted flrst in a loss of turgor and a slight wrinkling of the legion, followed by gradual flattening, leaving a faint, impalpable brownish dis- coloration of the skin of rather lesa than the area oovered by the pre-existing nodule. That this regression waa spontaneous and not related to the radiation therapy is indicated by the fact that the untreated nodules also subsequently underwent spon- taneous regression, passing through the same involutional stages as did those which had been treated. There have appeared a very few new nodulw, 80 that at the prea- ent time there are but 6 or 7 nodules in what may be d e d the f d l y developed atate.

The only treatment that has been tried, other than radium and carbon dioxide snow, has been along dietary lines. The 'child's total caloric intake haa been kept as low as has been consistent with normal growth and development, and the ratio of fat to protein and carbohydrate has been kept a little below that in his brother's and sisters' diet. His present weight (at thirty-four months) is 36 Ibs. 8 oe., his height

3 ft. 4 in., and he ie well developed apd nourished, with no excaw adipose tiesue. Previoae to the development of the lesions he had been given moderate doees, ffrst of md liver oil (3i per diem) and later of viosterol (gtt. X per diem), but theae warn stopped when the nature of the lesions was discovered.

The results of laboratory tests were as follows: Uln’ns, repeatedly negative for sugar and other abnormalities. Blood: R. B. C. 3,780,000; hemoglobin 86 per cent; birth Wassermann 0; fanting blood sugar 87 mg. per cent; fasting blood cholesterol 166 mg. per cent. Mim~copic Report on Biopey: Sections show the surface of the leaion covered by atratifled aquamoue epithelium, in some placea much thinned out and in others showing considerable papillary hypertrophy. The areolar tissue ie ftlled with oval and round cells, giant cells, and large foamy xanthoma cells. Some of the round oeh IUW undergoing mitosis. The xanthoma oelle are not frequent, but in the section appear quite deflnite. The giant cells are of the foreign body type and contain many nuolei, arranged near the periphery. Thew also have foamy cytaplasm in some instances.”

DISCUSSION CZirticaZ Aspects: Among the 120 cases of juvenile xanthoma

multiplex found in the literature, 102 were reported as occurring in children and 18 in adults whose lesions had first been observed before or during puberty. Approximately two thirds of the total number showed only the typical cutaneous nodular lesions, had no subjective symptoms, and were in good general health. The cu- taneous nodules were usually small and discrete, but occasionally confluent. In some reports they were described as reaching the size of a small bean. Even in cases with very numerous nodules the scalp, face, neck, and the extremities below the knees and elbows usually escaped involvement, though no part escaped in- variably. In the cases with less extensive distribution, the nodules tended to group themselves in clusters, mostly on the lower ab- domen, the buttmks, and the extensor surfmes of knees and elbows, less frequently on the chest, back, or shoulders. Cmes with extensive and those with slight involvement were equally free from subjective symptoms. Tenderness of the nodules, oc- casionally noted in adult cases by several of the earlier observers, was not a characteristic of the juvenile patients. Although the flattened, plaque-like, y,ellowish lesions on the eyelids, called xan- thelasma in contradistinction to xanthoma, nearly always occur in adults and very frequently in association with diabetes mellitus, such lesions were reported 9 times in this group of non-diabetic cases (de Vincentiis ; Poensgen ; Hyde ; Barlow ; Lehzen and Knauss ; Ehrmann ; Pollosson ; McDonagh ; and E. Schmidt).

One third of the patients showed, besides cutaneous lesions, one or more of a variety of other xanthomatous or related lesions. The most frequently associated condition was tendon sheath in- volvement, reported by Carry, Brachet and IMonnard, Barlow,

348 AETHUR B. MO OBAW

Lehzen and Knauss, Ehrmann, Arning, Pollitzer and Wile, and Burns. The tendon sheath lesions were usually multiple and af- fected most frequently the extensor tendons of the hands or the tendo Achillis. Aside from tendon sheaths, only a few other organs have been reported among children as showing xanthom- atous changes if we exclude examples of the Schiiller-Christian and Niemann-Pick syndromes, in which cutaneous xanthoma nodules are occasionally incidental parts of the grave systemic picture. In Virchow's original case there was xanthoma of the cornea. Seven patients had proved or suspected heart lesions, this group including the only two cases in which xanthomatous changes contributed to a fatal outcome (Lehzen and Knauss; Knowles and Fisher). In each of these two patients the mitral valve became stenosed by xanthomatous plaques, as shown at au- topsy. Of the remaining five, definite mitral atenosis was clinically demonstrable in three (Fox; Poensgen; Low), and only a heart murmur in the other two (Pollosson; Gwynne). In a patient de- scribed by Rhodes, laryngeal involvement necessitated tracheotomy. In one other case (Sibley) marked hoarseness suggested involve- ment of the larynx in some degree. Enlargement of the liver was noted by Crocker, Lehzen and Knauss, and Tor& Jaundice was observed by Lailler and Larraidy, Carry, Torok, and Gwynne. Enlargement of the spleen was noted by Torok. Of associated pathological conditions, the only outstanding one seem to be gout. In one case the patient suffered from the disease and in three others there was a family history (Colcott Fox, Barlow, and our own case). Merrill demonstrated slight cystic bone changes in roentgenograms of the phalanges, metacarpals, ulnae, and fibulae of his patient.

A familial occurrence of xanthoma involving brothers or sisters of the patient was noted in 12 reports (Burns ; Feulard ; Thibierge ; Mackenzie; Startin; Lehzen and Knauss; Gwynne; E. EMunidt; McDonagh ; Poensgen ; Ehrmann ; Wile ; Leskien). Xanthoma lesions in parents, grandparents, or more distant relatives were noted by Hyde ; Poensgen ; Ehrmann, and Staenglin. E. Schmidt '8 report of 5 brothers and sisters in one family is the outstanding example of the familial factor.

Course artd Treatment: In many of the reporte in the litera- ture, whether of adults or children, there is a disappointing dearth of information both as to treatment and as to the course of the affection whether treated or not. In two reports salicylic acid crystals and monochloracetic acid respeotively are mentioned as being used to remove one or two nodules. The use of the high- frequency current was mentioned by several of the earlier writers without much enthusiasm. Roentgen rays were mentioned as

JUVENILB XAXTHOMA MULTIPLEX 349

early as 1904 by Whitehouse, in 1907 by Sequiera, and in 1930 by Christie, Lyall and Anderson, but without definite information a8 to any benefit derived. Wherever cutaneous or tendon-sheath nodules were removed for histologic study, they did not tend to recur, and excision mas successfully used by Colcott Fox for cosmetic purposes and was recommended by Kaposi as the treat- ment of choice.

Of interest in connection with treatment is a tendency in some patients, as in our case, to spontaneous disappearance of the lesions. This tendency to regression is well recognized in cases of xanthoma diabeticorum, the parallelism between the control of the diabetes and the involution of the cutaneous lesions having been clearly demonstrated by Schamberg, Mook, Richter, and Wile. In certain non-diabetic cases, including our own, there has been defi- nite spontaneous regression of untreated lesions, first a softening, then a flattening, and finally a complete disappearance of the raised lesion, leaving only a tiny impalpable plaque of brown-stained scar. In five of McDonagh’s six cases spontaneous disappearance took place. Gwynne reports both disappearance and “reappear- ance,” but the Iatter may quite possibly be explained by the oc- currence of new lesions.

In recent years, in view of the results of newer biochemical investigations of the xanthoma problem, it has seemed logical to try to influence the course of the lesions through diet. Stetson in 1928 reported temporary improvement in a non-diabetic juvenile case on a low-fat diet, and Wile in 1929 studied two children (sisters) from the standpoint of a low caloric but otherwise bal- anced diet. He was able to cause marked temporary regression of the lesions, but only through a caloric reduction so extreme (to 400 calories per diem) as hardly to be recommended as a method of choice, particularly in a child. Since, however, any direct method of treatment, such as radium or excision, will have no in- fluence on the formation of new nodules, Wile’s idea appears fundamentally correct and we concur with him and with Rowland in advising a balanced diet, as low in total calories as is consistent with reasonable growth and development, and this in spite of ‘the fact that many of the patients included in this juvenile series were first seen as adults, after the lesions had persisted without regres- sion for many years.

Terminotogy: The majority of the earlier articles on xanthoma were purely descriptive in character, many of them the briefest of clinical reports. For many years after Addison and Gull in their first report coined the name “vitiligoidea,” terminology was a matter of interest and argument, Erasmus Wilson proposing

xanthelasma” and Virchow, “fibroma lipomatodes.” The term

880 ARTHUB B. M O OBAW

“xanthoma,” however, drat used by W. F. Smith in 1869, found most favor. Whether strictly correct or otherwise, it beosme the name of choice, and as different varieties of lesions were observed and reported, qualifying words such as “planurn, ” “tuberosum,” ccmultiplex,~y “disseminatum,” and “diabeticormn,” were added as aids to classilloation.

Histo2ogy Mcd Etiology: The clear description of the doro- scopic structure of the cutaneous nodule8 given by Virohow in 1871 stimulated a seriee of careful studies of the histology of xanthomatous lesions. Virchow considered the nodules benign neoplasms of connective-tissue origin, being followed in this con- ception, by Poensgen, McFarland, Landois and Reid, Garrett, Miller, and Wustmann. Torok accepted the neoplastic conception, but suggested an embryonic origin. McDonagh, in 1911, pyt for- ward the view of a benign neoplasm arising from endothehal tis- sue, a concept upheld by Aschod in 1925, The frequent associa- tion of diabetes with the flat yellowish plaques on the eyelids waa early ob8erved, and these lesions have for the most part been regarded as the result of a disturbed metabolism. In 1899, how- ever, and again in 1910, Pollitzer presented evidence suggesting the origin of xanthelasma from degenerating fibers of the orbiou- laris palpebrarum muscle.

From the beginning, histologic interest centered on the large cells which were recognized as typical of xanthomatous lesions. The foamy, reticulated appearance of the cells in fixed, stained seotions was found to be due to the dissolving out by the fixing agent of large, shining, yellowish droplets in the cytoplasm of the cells. It was generally assumed by earlier observers that these droplets were simply fat, although the presence of “doubly re- fractile droplets” in xanthoma cells was mentioned by Poensgen in 1883. In 1908 Pinkns and Pick proved the fat concept in error by demonstrating doubly refractile cholesterin ester as the substance of the droplets. This finding may fairly be considered the starting point for a series of histologic and, more particularly, bioohemical investigations which have led away from the neoplastic towards a humoral or metabolic concept of the xanthoma process. In 1912, influenced perhaps by the investigations of Pinkus and Pick, Pollitzer and Wile questioned the neoplastic nature of the cu- taneous nodules. Their idea was that the lesions were localized irritative tissue hyperplasias, affecting primarily the adventitial cells surrounding the smaller blood-vessel, followed by a secon- dary hyperplasia of the fixed connective-tissue cells, the whole process induced by an excess of cholesterol ester in the circulating blood, They believed that some of the excess cholesterol left the capillaries in areas where the latter were subject to speoial ten-

JUVENILB XANTHOMA MULTIPLEX 361

sions and stresses (knees, elbows, fingers, etc.), passed into the tissue spaces and was “taken up by the cells in the immediate neighborhood.” In 1913, J. M. H. Macleod supported this idea in a painstaking histologic study mentioning a proliferation of the endothelial cells of capillaries and an infiltration of these cells, as well as “the cells around the blood-vessels,” with lipoid material causing the characteristic foamy xanthoma cells. Macleod stated further that the irritative process did not stop with the formation of the xanthoma cells, but led to fibromatosis and the gradual transformation of a soft cellular proliferation into a hard fibrous mass. Further support of the non-neoplastic nature of xanthoma cells and an endothelial theory of their origin has been given ye- cently in the extensive studies and reviews of Arzt (1918), Herx- heimer (1927), Rowland (1928), Schaaf (1931), and Bloch (1931). The studies and opinions of .these authors have run parallel with and in part arisen from the concept of the so-called reticulo-endo- thelial system and its scavenging and storage function, inaugu- rated by Aschoff in 1913 and developed by him and by many others in subsequent years.

On the experimental side the theory of hypercholesterinemia as the underlying etiological factor in xanthoma was given strong support by the studies of Aschoff (1910), Kawamura (1911), Anitschkow (1913,1914,1924), Lebedew (1914), Bailey (1916), and McMeans (1916). I t was 1920, however, before the presence of an increased blood cholesterol in xanthoma was demonstrated in human subjects independently by Chauffard, Laroche and Grigaut, and by Burns. Numerous other observers co&rmed Chauffard’s findings, includiag Harrison, Beeson, Mook (1923), Herxheimer (1927), Stetson, Rowland (1928), Christie, Lyall and Anderson (1930), and Richter (1930). Further studies in experimentally produced hypercholesterinemia in animals and the lipoid storage thereby induced were carried out by Chalatow (1922), Zinserling (1923), Verse (1924, 1925), and Weidman (1924, 1927). Two pieces of interesting research along somewhat different lines were reported by Adlersberg (1925) and by Biedermann and Hofer (1931). The former studied the urine of a patient with general- ized santhomatosis, icterus, and splenomegaly, and found that if a twenty-four-hour period were divided into six parts, the specific gravity of the several specimens obtained was generally high with but slight fluctuations, the average surface tension appeared low with an abnormally small diurnal variation, and, in addition, a

1 Very recently another article by Rowland has been published in Vol. 4, Part 1, of the Ozford Yedioine. This is an amplification of hie previous investigations in 1028 and a comprehensive survey of the whole subject of disordered lipid metabolism, correlating the various syndromes ascribable to such disorder, and concluding with an extensive and useful bibliography.

352 ARTHUR B. MC G U W

considerable excess of bile acids appeared in the urine. Reasoning from these findings, he suggested that an increase of bile mids in the blood might affeot the solubility of the blood cholesterin, or increase the permeability of the capillaries to cholesterin. Bieder- mann and Hofer conducted tissue culture experiments using ma- terial from one of the xanthomatous areas in the parietal bone of a oase of the Schiiller-Christian syndrome. In 6 out of 30 oul- tures, through five transplantations for a total period of eighteen days, they observed the growth and multiplioation of large cells laden with doubly refractile, yellowish-brown pigmented droplets, resembling in appearance xanthoma cells in unstained tissue sec- tions. Connective-tissue cells of the same patient grown aa a con- trol in a similar medium failed to show any signs of resorbing lipids from the serum. Because of the brief time that their cul- tures grew, Biedermann and Hofer were unwilling to draw definite conclusions.

It remained, however, for Wile, Epkstein, and Curtis to show by a series of investigations in 1929 and 1930 that the theory of hyper- oholesterinemia cannot alone account for the formation of xan- thoma lesions. They studied the lipid chemistry of the blood and of the cutaneous and suboutaneous lesions in six patients of various ages, with various types of xanthomatosis, and pointed out that xanthoma can exist in the presence of a low or normal blood cholesterol value as well a? in the presence of a high blood choles- terol. They further found that the highest percentage of choles- terol in the total lipid content of any of the lesions they studied was but 48.81, the average for the remaining lesions being only 16.0. The percentage of cholesterol in the total solids of the lesions varied from 1.2 to 8.59. In the absence of diabetes, increase in alimentary fat had no influence on the course of cutaneous lesions but an extreme reduction in the total calories of a balanced diet brought about some regression (vide supra). In diabetes and potential diabetes, on the contrary, the appearance and disap- pearance of the nodular cutaneous lesions followed a rise and fall of the amount of circulating lipids, and dietary control of the diabetes was followed by complete regression of the lesions. Wile and his associates suggested that, disordered fat metabolism, in which cholesterol undoubtedly plays a part as a constituent of body lipids, is apparently responsible,” and that, “the nature of the lipid change in xanthoma is more dependent on the activity of the tissue thaq on the nature of the blood lipids.”

The etiological studies, however, which seem to us the most significant thus far reported, are those of Professor Bloch of Zurich and of his co-workers, Schaaf and Werner, published within the past year. Their series of personal cases numbered 9, includ-

JUVENILE UlOTHOMA MULTIPLEX 353

ing 4 of xanthoma palpebrarum, 3 of xanthoma disseminatum, and one each of xanthoma bulbi and of Schiiller-Christian’s disease. They studied the different components of the blood lipids of these patients, taking as approximate normal values a total lipid content of 750 to 800 mg, per cent; neutral fat, fatty acids, soaps 350 to 400 mg. per cent ; phosphatides 250 mg. per cent ; oholesterol 150 mg. per cent. Extending and amplifying Wile’s work and views, they have given convincing answers to some puazling questions. They first proved tho untenability of the hypercholesterinemia theory by demonstrating that in only 2 of their 9 patients was a high blood cholesterol present. In 4 it was low and in 3 normal. They pointed out, however, that this cholesterol value was made up of two fractions, free Cholesterol and cholestrol ester. Of these, the cholesterol ester constitutes normally 70 per cent of the total cholesterol and in none of the 9 cases was this normal per- centage exceeded, being normal twice and low seven times. It was further shown that the phosphatide component of the total blood lipids was also abnormal, being increased in every instance but one, in which the value was normal. When 4 of the subjects were given a dietary test of 5 grams of cholesterol in 100 grams of olive oil, the reactions in every case deviated from that of a normal control. Analyzing the above findings in the light of the fact that the con- centration of cholesterol ester for optimum stability of a choles- terol, cholesterol ester, water emulsion is 60 per cent of the total (virtually the same as that in normal human serum), Bloch, Schaaf, and Werner reached the conclusion that in patients with xanthoma there exists a greater or less disturbance of that mech- anism which regulates, by maintaining an optimum concentration of tbe various lipid components, the stable emulsion of fat and lipids in the blood serum. If this balance is upset, partial pre- cipitation of one or more fractions will occur in order that the balance may be re-established. The precipitated portions are thus set free in the tissue spaces with the resulting necessity for disposal, in the form of storage, by the reticulo-endothelial cells available for that purpose. The authors frankly admit their inability to describe or localize this regulating mechanism and propose no theory, but suggest the liver as the most likely location. They further point out that in the study of patients with xanthom- atous lesions, blood cholesterol or blood fat determinations alone are of no value. Fractional analysis of the various lipid constit- uents must be made both in fasting subjects and after the intro- duction of an excess load of fat and cholesterin by test meal. We hope to carry out and report such studies on our own patient when he is a few years older.

364 ARTHUB B. M O ORAW

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