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Diffuse Gastrointestinal Polyposis with Ectodermal Changes
Vol. 50, No.1 Printed in U.S.A.
GASTROENTEROLOGY
Copyright © 1966 by The Williams & Wilkins Co.
DIFFUSE GASTROINTESTINAL POLYPOSIS WITH ECTODERMAL CHANGES A case with severe Illalahsorption and enteric loss of plasllla proteins and electrolytes STIG JARNUM, M.D., AND HERLUF JENSEN, M.D. Medical Department P, Gastroenterological Division, Rigshospitalet, Copenhagen, Denmark
Polyposis of limited regions of the alimentary tract has been known for many years. Menetrier 1 gave the first description of gastric polyposis-polyadenomes polypeux-in 1888. Familial polyposis of colon is now recognized as a distinct disease entity, and small intestinal polyposis is well known as the most important clinical component of Peutz-Jeghers' syndrome. 2 ,3 However, extensive polyposis including the entire or at least all parts of the gastrointestinal tract is rare. Only six cases have been reported with certain extraordinary associated ectodermal changes. The eponym for this condition, Cronkhite-Canada's syndrome,4 is derived from the names of those who first described it. The ectodermal changes consist of alopecia, nail atrophy, and, hyperpigmentation. We now present a seventh case in whom we were able to demonstrate an excessive enteric leakage of plasma proteins and probably calcium, magnesium, and potassium as well. Case Report The patient was a 58-year-old married woman. Her family history was negative, particularly with regard to gastrointestinal and dermal diseases. As a child she was operated on Received June 5, 1965. Accepted August 20, 1965. Address requests for reprints to: Dr. Stig Jarnum, Medical Department P, Rigshospitalet, Copenhagen, Denmark. This investigation was supported by Research Fellow Grant 7 R05 TW-00157-01 from the National Institutes of Health and by Kpbmand i Odense Johan Weymann og hustru, fpdt Seedorff's grant.
for a pulmonary abscess, and some years later a lymph node was removed from the neck. A benign tumor was extirpated from the left breast when she was 42 years old. In 1964, a few months before the present disease, a benign polyp was removed from the cervix. The present complaints began March 1964, 6 months before the patient was seen in this hospital. The initial symptoms were xerostomia, loss of taste, anorexia, and weight loss. After a month she developed diarrhea with up to 15 watery light brown stools a day with abdominal pain, nausea, and vomiting. At the same time she noticed increasing pigmentation of the skin and suffered a total loss of scalp hair, all fingernails, and some toenails. From March until October 1964 she underwent several hospital admissions during which a considerable number of investigations were undertaken. They led to the conclusion that extensive pathological lesions were present in the stomach and the colon, lesions which resulted in a malabsorption syndrome with hypocalcemia, hypokalemia, and hypoproteinemia. Several tentative diagnoses, including ulcerative colitis, thallium poisoning, and amebic dysentery, were suggested. A short course of steroid treatment and, later, emetine, was unsuccessful. In October 1964, an emergency admission to the local hospital was necessitated by a sudden adynamia of skeletal muscles. On the following day she developed muscular cramps and stiffness of her arms and fingers. The serum calcium and serum potassium were found to be 4.8 mg per 100 ml and 2.9 meq per liter, respectively. She was treated both orally and parenterally with calcium and potassium with some effect, but the serum concentrations remained low. One week later the patient was transferred to this hospital. On admission she complained of muscular weakness and diarrhea. She passed up to 2000 ml of watery, light brown stools daily.
107
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FIG. 1 (left). Scalp with alopecia of Case 7. FIG. 2 (right). Atrophy of fingernail.
Physical examination revealed an undernourished, dehydrated woman with pale mucous membranes in contrast to a pronounced and diffuse brown pigmentation of the skin. Temperature, pulse rate, and blood pressure were 37.6 C, 84 per min, and 95/60 IDID Hg, respectively. The scalp hair was scanty (fig. 1), but some had grown out since the initial complete loss. Axillary and pubic hair were almost absent. The finger- and toenails were replaced by fragile halfgrown nails (fig. 2). A moderate pitting edema of the legs and lumbar region was present. Ophthalmological examination showed arteriosclerotic retinal vessels and senile degeneration of the left macula but no exudates or pigmentation. The neurological examination revealed positive Trousseau, Chvostek, and Lust's signs, diffuse atrophy of the muscles, and an absent tendon reflex of the left heel. Rhinological examination showed no nasal polyps. A pelvic examination was normal. Laboratory investigations showed severely depressed serum concentrations of potassium, calcium, magnesium, and protein, especially albumin (table 1). ECG showed low voltage. The hemoglobin was 7.4 g per 100 ml,
erythrocyte sedimentation rate, 16 mm in 1 hr; white cells, 6900 per ,uliter with a normal differential count; thrombocytes, 265,000 per ,uliter; and eosinophiles, 44 per ,uliter. Serum iron was 140 ,ug per 100 ml; total iron-binding capacity, 206 ,ug/100 ml; and folic acid, 0.006 ,ug per ml. Serum proteins. Total protein was 4.07 g per 100 ml; albumin, 1.57 g per 100 ml; a,-g10bulin, 0.46 g per 100 ml; a2-g10bulin, 0.65 g per 100 ml; ,a-globulin, 0.57 g per 100 ml; and y-globulin, 0.82 g per 100 ml; prothrombin, 910/0; acetylcholinesterase, 0.59 ,umoles per min per ml (normal values, 3.2-5.7). Haptoglobin, fibrinogen, and ceruloplasmin were all normal. Immune electrophoresis showed the presence of all immune globulins, an increase of a2-macroglobulin and a decrease of transferrin, a glycoprotein, " and albumin. Hepatic function tests. Serum bilirubin, alkaline phosphatase, and thymol turbidity were normal. A hepatic biopsy revealed the presence of a considerable amount of hemosiderin in the liver cells, but was otherwise normal. Renal function. Serum creatinine and serum urea were normal. There was no protein, blood,
109
CASE REPORTS
January 1966
or sugar in the urine, and the sediment was normal. Gastrointestinal function tests. These tests showed steatorrhea with a maximal fat excretion of 32.9 g per day. A Schilling test was abnormal both with and without added intrinsic factor (4.5 and 1.6%, respectively). Urinary 5 HIAA excretion was normal. Achlorhydria was present on augmented histamine test. Pancreatic function test (after Borgstrom') showed a slightly depressed function. Stool cultures revealed no tubercle bacilli or salmonella. Hormones and vitamins. Urinary excretion of 17 ketosteroids and 17 hydroxycorticosteroids was normal. Protein-bound iodine was slightly depressed (2.7 p.g per 100 ml). However, the concentration of diffusible thyroxine determined on a later occasion was normal. Thiamine tolerance test, serum ascorbic acid, and serum B12 all showed normal values. Radiological findings. Examination of the upper gastrointestinal tract revealed an extraordinary pattern with numerous, fine, polypoid filling defects in the stomach and duodenum (fig. 3) . No ulcer or tumor was seen. A barium enema similarly showed many defects in the entire colon. There were multiple polyps varying in size from 5 to 10 mm. The haustral folds were normal (fig. 4). A small intestinal series revealed coarsening of the mucosa. With the possible exception of the proximal jejunum (fig. 3), no alterations similar to those found in the stomach, duodenum, and colon were present. Cholecystography (fig. 4) and intravenous pyelography were normal. Sigmoidoscopy demonstrated multiple polyps and hypertrophy of the mucosal membrane. The lesions were more pronounced in' the sigmoid than in the rectum. A few punctate hemorrhages, but no ulcerations were seen. No rigidity was observed. A biopsy of a rectal polyp showed only cystlike dilations of several glands. A skin biopsy from a nonpigmented area was normal. From an area with hyperpigmentation a marked and regular accumulation of pigment was present in the basal epithelial layer. The pigment looked like melanin. An increased number of "clear cells" were also seen.
TABLE
1. Laboratory data before and following conservat1've treatment
I Hemoglobin (g/100 ml) Serum protein (g/100 ml) Serum albumin (g/100 ml) Serum sodium (meq/liter) Serum potassium (meq/liter) Serium calcium (mg/100 ml) Serum phosphorus (mg/100 ml) Serum magnesium (meq/liter) Stools (g/day) Fecal fat (g/day) Weight (kg)
October
1964, on
first admission
December 1964, after treatment
I
January 1965, on second admission
7.4
10.1
9.0
4.07
4.6
2.97
1.57
2.0
0.50
133
136
131
2.9
4.5
4,5
4.7
7.4
6.2
2.9
3.2
0.7
1.4
2000 45.7 52.7
600 51. 7
I
I
3,0 1.3 1300 74 57.2
Subsequent Course Initially, the patient received parenteral nutrition with fluid, electrolytes, fat emulsions, and amino acids. Since she was anemic and her stools gave a consistently positive benzidine re-
FIG. 3. Radiogram showing polypoid filling defects in the stomach and coarsening of the mucosa in the proximal jejunum. Mucosal prolapse is present in the pylorus.
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FIG. 4. Radiogram after barium enema. Numerous filling defects are present in the colon. Note the visualization of the gall bladder after a previous cholecystography. The gall bladder contains no polyps. action, transfusions of blood and plasma were given. No overt hemorrhage was present. Later she was placed on intensive substitution therapy including biweekly injections of calcium, magnesium, vitamins, and daily oral supplements of potassium (54 meq) , calcium (1150 mg), and vitamin D (2000 IU, later 300,000 IU). Opium was given daily to keep the number of movements to a minimum. A planned low fat diet had to be cancelled because of the patient's reluctance to change her dietary habits. In an attempt to eradicate a possible abnormal bacterial flora within the gastrointestinal tract she was unsuccessfully treated with tetracycline and a yogurt preparation. Since the radiological examinations and the gastrointestinal function tests revealed extensive lesions all through the alimentary tract, it was decided to perform a temporary ileostomy. By doing so it could be established whether the colon represented the major route of electrolyte and protein loss and, if so, a colectomy might be beneficial to the patient. However, shortly after the transfer to the surgical department the patient underwent a marked improvement which was reflected by the laboratory tests 7 weeks after admission (table 1).
Considering the fact that no radical treatment was possible, she was discharged on substitution therapy. The improvement was not of long duration. One month later she was readmitted, and from then on her condition rapidly deteriorated. Fecal fat was more than twice as high as on thEl first admission. Her serum albumin had dropped to a level of 0.50 g per 100 ml and edema of the legs and back was present (table 1). An emergency subtotal colectomy was performed at which time steroids were administered. The wall of the stomach was thick and edematous. When a small gastrotomy was made on the anterior wall of the antrum, a large number of fingerlike, \12- to 2-cm long polyps protruded through the opening. A biopsy showed polypoid tissue with a mucin-producing epithelium and a large number of grossly dilated glands in the stroma. The small intestine appeared grossly normal. On palpation, however, it was felt to be granular. A biopsy of the proximal jejunum and of the distal ileum revealed that the villi were blunted and sparse. No polyps in the strictest sense were seen. Surprisingly, microscopy showed a severely distorted structure of the mucosa.
January 1966
CASE REPORTS
111
FIG. 5. High power magnification of biopsy from the ileum. A single normal villus is present (X 210).
The villi were scanty and short and many cystlike glands were seen in the lamina propria (fig. 5). The resected colon was cut open longitudinally. The appearance of the mucosa was highly abnormal. The transverse folds were €xtremely hypertrophic, and at many places large numbers of small bluish polyps with a -diameter up to 2 cm were present (fig. 6). Again the microscopic picture was dominated by di1ated glands and cysts (fig. 7). Many of the cysts were filled with inspissated material. Similar, though much less pronounced Dhanges were present in the appendix. The liver, gall bladder, pancreas, and kidneys were found normal during the operation. The postoperative course was brief. For a few days her condition remained stable. Then she developed increasing gastric retention and signs of ileus. Re-exploration revealed no mechanical obstruction. She died rather suddenly from pulmonary embolism 7 days after the co1ectomy and 10 months after the onset of her disease. Autopsy revealed a fresh pulmonary embolism. In the esophagus a number of 1- to 2-mm broad mucosal prominences were present. No
other macroscopic lesions not already recognized during laparotomy were seen. On microscopy the liver displayed a fatty metamorphosis. The lamina propria of the jejunum contained an increased amount of fibroblasts and collagen fibers. Otherwise, nothing new was revealed. The esophagus appeared normal. The skin contained atrophic hair follicles .
Special Investigations Cr51-albumin. Crs1 -albumin (ca. 20 /Lc), prepared according to the method described by Waldmann,6 was injected intravenously during the first admission. The fecal excretion of Cr51 in a succeeding 4day period amounted to 5.5% of the injected dose (normal, less than 1%). Thus the test demonstrated an abnormal gastrointestinal plasma protein loss. Ji31- albumin study. This study was performed 1 week later with a preparation made after McFarlane's monoiodine chloride method. 7 Part of the injected dose (a total of ca. 50 /Lc) was inadvertently deposited in the subcutaneous tissue. Conse-
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CASE REPORTS
Vul. 50, No.1
FIG. 6. Colon after it was removed and cut open. Prominent hypertrophic folds and scatt ered polyps are present all through the specimen.
FIG. 7. Histological picture of a colonic polyp. The "cysts" contain a granular inspissated material.
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CASE REPORTS
January 1966 TABLE
2. Plasma protein turnover studies J13'-albumin
Observed value
Plasma volume (Ull) Serum concentration (g/ lOO ml) Intravascular mass (I.V.M.) % of total mass Fractional catabolic rate, % of I.V.M./ day Synthetic rate (g/day) Fecal excretion of the label , % of injected dose/ 4 days
1.86
Normal range
4.44-5.86
Observed value
Norm,l range
Observed value
Normal range
5.5
<1.0
2900 1890-3670 0.96 0.62-1.10 52.8 41-63
17.0
6-14
21.1
5.8- 7.4
9 .2 8 .8
8-15 <0.5
5.9 18.2
1.0-3.9 <0.5
quently it was not possible to calculate the pool distribution. However, the metabolic clearance could be established after the method of Pearson et al. 8 The P :H-albumin degradation rate amounted to 17.0% of the intravascular pool per day (r..ormal value, 6 to 14) (table 2). Assuming steady state conditions and an un denatured tracer substance, this figure indicated a synthetic rate -of 9.2 g per day or 0.19 g per day, which fell within normal range (0.16 to 0.24 g per kg per day). A remarkable feature was the large ~mount of label, 8.8% of the injected dose, -excreted in the stools in 4 days (normal figure, < 0.5%). J125- yG - globulin turnover. YG-Globulin was isolated on a diethylaminoethyl (DEAE) -column 9 and subsequently labeled with p25 after McFarlane. 7 Approximately 20 fJ-c were given intra-venously and the turnover calculated after Matthews. 10 The degradation rate (table 2) was 21.1 % of the intravascular pool per -day (normal values, 4.2 to 9.6).9 The synthetic rate was high, 5.9 g per day (normal, 1.0 to 3.9). The total y-globulin fraction as -determined by paper electrophoresis was applied in the calculation. The distribution ratio calculated according to Nosslin l l was 52.8; i.e. 52.8% of the total YG-globulin pool was located in the blood stream. This figure was normal (normal values, 41 to 63) . The fecal p25 excretion was 18.2% of the injected dose in 4 -days, an extremely high figure (normally Jess than 0.5%) .
Cr51 -albumin
JI2''YG_globulin
Paper electrophoresis of gastric secretion revealed the presence of small amounts of several protein fractions. The YG-globulin concentration determined immunochemically was about 0.3 g per 100 ml both in gastric secretion and in the stools. (Immunochemical determination of YG-globulin was performed by Dr. J ¢rgen Clausen, Institute of Biochemistry, Copenhagen.) Gastrointestinal Loss of Electrolytes Stomach. The samples aspirated during augmented histamine test were analyzed for electrolytes. The values of five individual collecting periods of 15 min were very similar. If recalculated as daily loss they amounted to 9 meq of potassium, 1.2 meq of magnesium, and 63 mg of calcium per 24 hr. This would presumably represent figures of maximal loss and did not indicate any appreciable loss of these electrolytes via the stomach. Intestine. Due to the patient's unstable condition it was impossible to perform proper balance studies. Several fecal analyses were made. On days with a large stool volume, as much as 3.80 g of calcium and 27 meq of magnesium were lost by this route as compared with an oral intake of 2.34 g of calcium (including 1.15 g in tablets) and 11.4 meq of magnesium. Discussion
Cronkhite and Canada 4 in 1955 reported two cases of diffuse gastrointestinal polyposis associated with alopecia, nail atrophy, and hyperpigmentation. A similar case was
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CASE REPORTS
published in 1961 by Kennedy and Hirson. 12 They described their patient as "a transient syndrome with Peutz-Jeghers features and ectodermal change." However, several features typical of PeutzJ eghers' syndrome were missing. The disease made a late debut, there was no family history, and no mucosal pigmentation. In fact, having skin, nail, and hair changes together with diffuse gastrointestinal polyposis, the patient displayed a typical Cronkhite-Canada's syndrome. Martini and Dolle 13 reported three cases of Menetrier's syndrome, a designation most often used synonymously with giant hypertrophic gastritis. One of the patients died. At autopsy diffuse polyposis was present in the stomach, small intestine, and the whole colon. In addition the patient had ectodermal lesions in the form of "mycosis" of finger- and toenails. Consequently, it was felt justified to include the case in the present survey. Johnston et al.H and Zdansky and Riederer 1:> each published a typical case. Thus, the present one seems to be the seventh. Table 3 compares clinical and radiological data in the seven reported cases. They were all middle-aged or elderly patients. Six were women. All except one (no. 6) had diarrhea, and in four it was the initial symptom, whereas a loss of taste was the first complaint in two. The course was fatal within a period of 6 to 18 months in five cases. They died in a state of severe cachexia. One patient (no. 3) was an extraordinary exception, because she underwent a complete remission within 2Y2 months. 12 Another case (no. 6), the only male,15 apparently underwent a complete recovery following right-sided hemicolectomy, which was performed as an emergency operation because of an intussusception. The roentgenograms revealed gross alterations compatible with extensive polyposis in the stomach and in the colon. In four cases (nos. 1, 3, 5, 6) polyps were suspected on the small intestine although no polyps in the strictest sense were present. In the esophagus a very limited number of small polyps were found in Case 3 (radiologically) and Case 7 (at autopsy).
Vol. 50, No.1
Laboratory data are depicted in table 3. Normal serum proteins were present in Case 3, in whom the syndrome was transitory, in five patients serum proteins were low, and in the remaining case (no. 1) serum protein values were not given. It was reported, however, that this patient gradually accumulated considerable edema of her legs. The hypoproteinemia in these patients was notably a hypoalbuminemia. Since hepatic function tests were normal and proteinuria was absent (case nos. 1-3,5,7), an underlying gastrointestinal protein loss seemed highly probable as suggested by Johnston et al.14 Martini and Dolle 13 demonstrated an abnormal fecal pS1_ polyvinylpyrrolidone excretion (3.28 % of the inj ected dose, normally less than 1%) in their case (no. 4) as evidence of an abnormal gastrointestinal protein loss. In the present case, Johnston's suggestion also proved to be correct as demonstrated by means of Cr51-albumin (table 2). In gastric aspirations during augmented histamine test no Cr51 was present. Therefore gastric protein loss was probably negligible, and the abnormal protein loss must have proceeded at a lower level of the alimentary tract. The fecal recovery of large amounts of radioactive iodine in the turnover studies with iodine-labeled albumin and YG-globulin was strong evidence that the colon represented the most important site of plasma protein loss.16 Actually, this finding underlay the rationale to perform a colectomy. Serum calcium and serum potassium were depressed in the four cases (nos. 2, 4, 5, 7, table 3) in whom they were determined, and in our case to such an extent that both muscular weakness and tetanic manifestations occurred. A pronounced hypomagnesemia was an associated phenomenon at least in our case. Her tetanic symptoms did not vanish until parenteral calcium therapy was supplemented with magnesium. It seems reasonable to assume that the electrolyte deficiencies were at least partially due to intestinal loss. Although no proper balance studies have been performed in any of these patients, a net loss
8
Generalized
Fatal
F,42 Diarrhea
2~2'
Spontaneous recovery
F,69 Anorexia, loss of taste 18
-------
3.3
6.4
6
M,54 Abdominal pains, nausea
Case 6
F,58 Loss of taste
Case 7
"Normal"
2.9
0.7
2.9
4.3
10 >6 Apparent recov- Fatal ery after hemicolectomy Stomach, ileum, Stomach, duo- Stomach, duodenum, jejudenum, colon, colon, rectum num, colon rectum 5.4 4.15 4.1 3.4 1.95 1.6 Fatal
2.0
8.5-->3.8
4.3 ca. 1.6
Stomach, colon
Fatal
2.6
"Normal"
Case 5
F,71 F,51 Edema of the Diarrhea, legs, diarrhea alopecia
Case 4
1.2
4.8
Stomach, duo- Generalized denum, colon, rectum 3.3 "Normal" 1.1 "Normal"
F,75 Diarrhea, transient pigmentation 9 yr before 17 Fatal
Case 3
a
Clinical and laboratory data: Cases 1 and 2, Cronkhite and Canada, 1955;4 Case 3, Kennedy and Hirson, 1961 ;12 Case 4, Martini and Dolle, 1961 ;1' Case 5, Johnston et a!., 1962;14 Case 6, Zdansky and Riederer, 1963;15 Case 7, Jarnum and Jensen (prc3ent case).
Serum protein (g/100 ml) Serum albumin (g/100 ml) Serum calcium (mg/lOO ml) Serum phosphorus (mg/ 100 ml) Serum magnesium (meq/ liter) Serum potassium (meq/ liter)
Radiological extension of polyposis
Duration (mo) Outcome
Sex, age Initial symptom
Case 2
3. Diffuse gastrointestinal polyposis with ectodermal changes (Cronkhite-Canada's syndrome)a
Case 1
TABLE
C,;(
.....
~
~
o
~
~ ~
~
'<::
....
£;
~.:
116
CASE REPORTS TABLE
Vol. 50, No.1
4. Gastrointestinal function tests
Schilling's test Case no.
Achlorhydria
With Without intrinsic intrinsic factor factor
Pancreatic function test
n-Xylose test
Glucose tolerance Steatorrhea t est
- - - - --
1 2
3
4 5 6
7
+
%
? Histamine-fast
Histamine-f ast Histamine-fast No + (Augmented histamine test)
gjday
g
%
Normal Flat curve Normal
Trypsin present in duodenal aspirate
I Normal 1.6
4.5
Slightly subnormal amylase concentrations In duodenal aspirates
of 1.5 g of calcium and 16 meq of magnesium was found in the feces of the present case on a day with a large, but not exceptional stool volume.
Gastrointestinal Function Tests Achlorhydria was present in at least five patients (table 4). Few absorption studies were made. Steatorrhea was present in one case (no. 7), absent in another (no. 5), and not mentioned in the remaining five cases. Also, the glucose tolerance test was normal in some and abnormal in others. An-xylose test was highly abnormal in the present case as was a B12 absorption test both with and without added intrinsic factor. Altogether, there could hardly be any doubt that malabsorption was more pronounced in the present case than in the others. It agreed well with the severe histopathological lesions found in the small intestinal mucosa (fig. 5). Pancreatic function was essentially unchanged in the two cases examined (nos. 3 and 7). Pathological Lesions In the present case gross macroscopic alterations were present in the stomach (numerous large polyps) and in the colon (tremendous hypertrophy of the transverse folds with scattered polyps), whereas the small intestine did not present any polypoid
1.6
Flat curve
No
45.7
lesions, although a marked villous atrophy was evident through a magnifying glass. Quite contrary to the macroscopic picture, the histological lesions were surprisingly uniform throughout the gastrointestinal tract. An intact epithelium, tortuous glands, and cysts of varying size occurred at all sites. In the colon the cysts often contained a granular material suggesting the presence of protein. At autopsy of Case 4 an almost identical histological picture was found all through the gastrointestinal tract. 13 Also in Case 5 a similar picture was seen in a rectal polyp.14 Cronkhite and Canada reported that in Case 1 "the lesions in the gastrointestinal tract were consistent with simple adenomatous polyps" (autopsy finding), and in Case 2 a biopsy from a sigmoid polyp showed a benign adenomatous polyp. In no instance was there any evidence of malignancy, lymphatic involvement or inflammatory process; i.e. lesions which most often underlie an abnormal gastrointestinal protein loss.
Etiolgoy The etiology of Cronkhite-Canada's syndrome remains obscure. The fact that the syndrome in one case,12 although fully developed, underwent a complete remission, suggests that exogenous agents may be involved. Also, there seemed to exist no hereditary basis in any of the cases. In this
CASE REPORTS
January 1966
117
respect, the syndrome deviates from other and at autopsy. The macroscopic picture .syndromes of gastrointestinal polyposis as- was different at various sites (polyps in the sociated with ectodermal changes, e.g. 'stomach, villous atrophy in the small inPeutz-Jeghers' syndrome with small in- testine, hypertrophic rugae with scattered testinal polyposis and mucocutaneous polyps in the colon). In contrast, the mifrecklelike pigmentation2 , 3 and Gardner's croscopic picture was highly uniform and .syndrome with nondiffuse colonic polyposis characterized by cystlike dilations of the glands. and epidermoid cystS. 17 The ectodermal changes were nonspeThe etiology of the syndrome remains ·cific in the sense that each component obscure. The ectodermal changes seem to could be referred to some biochemical de- be an inherent part of the syndrome and rangement or nutritional deficiency state not secondary to malabsorption. due to malabsorption. Hyperpigmentation is a symptom in pellagra, and hair and nail REFERENCES changes may occur in states of prolonged 1. Menetrier, O. 1888. Des polyadenomes gastrihypocalcemia and-in animal experiments ques et de leurs rapport avec Ie cancer de -hypomagnesemia. l'estomac. Arch. Physiol. Norm. Path 1: However, it is improbable that this was 32-55. the mechanism in the patients. First, one 2. Peutz, J. C. A. 1921. Over een zeer merkpatient with transitory lesions 12 had norwaardige, gecombineerde familiaire polymal serum electrolyte values and no malabposis van de slijmvliezen van den Tractus sorption. Second, steatorrhea was also intestinalis met die van N eusheelholte en tLbsent in Case 5 (table 4). 8 Thirdly, the gepaard met eigenaardige pigmentalies van hind.-en slijmvliezen. Nederl. Maandschr. ectodermal changes developed at such an G2neesk. 10: 134-146 . .early stage compared to other malabsorp3. Jeghers, H., V. A. McKusick, and K. H. tive manifestations that a true deficiency Katz. 1949. Generalized intestinal polystate could hardly exist at the time when posis and melanin spots of oral mucosa, they made their appearance. Therefore, it lips and digits; syndrome of diagnostic is reasonable to conceive that the ectodersignificance. New Eng. J. Med. 241: 993mal changes were an inherent part of the 1005. syndrome. 4. Cronkhite, L. W., and ,Yo J. Canada. 1955. Summary
A case of Cronkhite-Canada's syndrome is presented. The syndrome, which is extremely rare, is characterized by diffuse gastrointestinal polyposis, alopecia, nail atrophy, and hyperpigmentation of the skin. Severe malabsorption, hypoproteinemia, and marked depression of serum calcium, magnesium, and potassium were additional features. It could be shown by means of labeled proteins that large amounts of albumin and I'G-globulin leaked into the intestinal tract and, in particular, into the colon, whereas gastric protein loss was negligible. Also, although no proper balance studies could be carried out, evidence of an intestinal net loss of electrolytes was present. Severe lesions of the entire gastrointestinal tract were found during laparotomy
5.
6.
7.
8.
9.
Generalized gastrointestinal polyposis. An unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. New Eng. J. Med. 252: 1011-1015. Borgstriim, B., A. Dahlqvist, G. Lundh, and J. Sjiivall. 1957. Studies of intestinal digestion and absorption in the human. J. Clin. Invest. 36: 1521-1536. Waldmann, T. A. 1964. The preparation of chromium51 labelled albumin. Panel on radioisotope techniques in the study of protein metabolism. 1. A. E. A. Vienna, June 1964. McFarlane, A. S. 1958. Efficient trace-labelling of proteins with iodine. Nature (London) 53: 182-183. Pearson, J. D., N. Veall, and H. Vetter. 1958. A practical method for plasma albumin turnover studies. Radioakt. Isotope Klin. Forsch. 3: 290-297. Andersen, S. B. 1964. Metabolism of human gamma globulin (gammass-globulin), p. 31. Blackwell Scientific Publications, Oxford.
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CASE REPORTS
10. Matthews, C. M. E. 1957. The theory of tracer
experiments with Pal-labelled plasma proteins. Phys. Med. Biol. 2: 36--53. 11. Nosslin, B. Cited in ref. 9, p. 115. 12. Kennedy, J. A., and C. Hirson. 1961. A transient syndrome with Peutz-Jeghers features and ectodermal change . Proc. Roy. Soc. Med. 54: 234-235. 13. Martini, G. A., and W. Dolle. 1961. Menetrier-Syndrom. Polyadenomatosis des Magens mit Eiweissverlust in den MagenDarm-Kanal. Deutsch. Med. Wschr. 86: 2524-2530. 14. Johnston, M. M., J. W. Vosburgh, A. T. Wiens, and G. C. Walsh. 1962. Gastrointes-
Vol . 50, No . 1
tinal polyposis associated with alopecia, pigmentation and atrophy of the fingernails and toenails. Ann. Intern. Med. 56: 935-940. 15. Zdansky, E., and J. Riederer. 1963. Gastro-
intestinale polypose Adenomatose mit Hypoproteiniimie und ektodermalen Storungen. Radiol. Clin. (Basal) 32: 254-263. 16. Jarnum, S. 1961. Fecal P'l1- output after intravenous injection of I131-labelled human serum albumin in normo- and hypoproteinemic subjects. Scand. J. Clin. Lab. Invest. 13 : 462--475. 17. Gardner, C. McG. 1948. Polyposis of the colon. Arch. Surg. (Chicago) 56: 75-78.
GASTROENTEROLOGY
Copyright © 1966 by The Williams & Wilkins Co.
DIFFUSE GASTROINTESTINAL POLYPOSIS WITH ECTODERMAL CHANGES A case with severe Illalahsorption and enteric loss of plasllla proteins and electrolytes STIG JARNUM, M.D., AND HERLUF JENSEN, M.D. Medical Department P, Gastroenterological Division, Rigshospitalet, Copenhagen, Denmark
Polyposis of limited regions of the alimentary tract has been known for many years. Menetrier 1 gave the first description of gastric polyposis-polyadenomes polypeux-in 1888. Familial polyposis of colon is now recognized as a distinct disease entity, and small intestinal polyposis is well known as the most important clinical component of Peutz-Jeghers' syndrome. 2 ,3 However, extensive polyposis including the entire or at least all parts of the gastrointestinal tract is rare. Only six cases have been reported with certain extraordinary associated ectodermal changes. The eponym for this condition, Cronkhite-Canada's syndrome,4 is derived from the names of those who first described it. The ectodermal changes consist of alopecia, nail atrophy, and, hyperpigmentation. We now present a seventh case in whom we were able to demonstrate an excessive enteric leakage of plasma proteins and probably calcium, magnesium, and potassium as well. Case Report The patient was a 58-year-old married woman. Her family history was negative, particularly with regard to gastrointestinal and dermal diseases. As a child she was operated on Received June 5, 1965. Accepted August 20, 1965. Address requests for reprints to: Dr. Stig Jarnum, Medical Department P, Rigshospitalet, Copenhagen, Denmark. This investigation was supported by Research Fellow Grant 7 R05 TW-00157-01 from the National Institutes of Health and by Kpbmand i Odense Johan Weymann og hustru, fpdt Seedorff's grant.
for a pulmonary abscess, and some years later a lymph node was removed from the neck. A benign tumor was extirpated from the left breast when she was 42 years old. In 1964, a few months before the present disease, a benign polyp was removed from the cervix. The present complaints began March 1964, 6 months before the patient was seen in this hospital. The initial symptoms were xerostomia, loss of taste, anorexia, and weight loss. After a month she developed diarrhea with up to 15 watery light brown stools a day with abdominal pain, nausea, and vomiting. At the same time she noticed increasing pigmentation of the skin and suffered a total loss of scalp hair, all fingernails, and some toenails. From March until October 1964 she underwent several hospital admissions during which a considerable number of investigations were undertaken. They led to the conclusion that extensive pathological lesions were present in the stomach and the colon, lesions which resulted in a malabsorption syndrome with hypocalcemia, hypokalemia, and hypoproteinemia. Several tentative diagnoses, including ulcerative colitis, thallium poisoning, and amebic dysentery, were suggested. A short course of steroid treatment and, later, emetine, was unsuccessful. In October 1964, an emergency admission to the local hospital was necessitated by a sudden adynamia of skeletal muscles. On the following day she developed muscular cramps and stiffness of her arms and fingers. The serum calcium and serum potassium were found to be 4.8 mg per 100 ml and 2.9 meq per liter, respectively. She was treated both orally and parenterally with calcium and potassium with some effect, but the serum concentrations remained low. One week later the patient was transferred to this hospital. On admission she complained of muscular weakness and diarrhea. She passed up to 2000 ml of watery, light brown stools daily.
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FIG. 1 (left). Scalp with alopecia of Case 7. FIG. 2 (right). Atrophy of fingernail.
Physical examination revealed an undernourished, dehydrated woman with pale mucous membranes in contrast to a pronounced and diffuse brown pigmentation of the skin. Temperature, pulse rate, and blood pressure were 37.6 C, 84 per min, and 95/60 IDID Hg, respectively. The scalp hair was scanty (fig. 1), but some had grown out since the initial complete loss. Axillary and pubic hair were almost absent. The finger- and toenails were replaced by fragile halfgrown nails (fig. 2). A moderate pitting edema of the legs and lumbar region was present. Ophthalmological examination showed arteriosclerotic retinal vessels and senile degeneration of the left macula but no exudates or pigmentation. The neurological examination revealed positive Trousseau, Chvostek, and Lust's signs, diffuse atrophy of the muscles, and an absent tendon reflex of the left heel. Rhinological examination showed no nasal polyps. A pelvic examination was normal. Laboratory investigations showed severely depressed serum concentrations of potassium, calcium, magnesium, and protein, especially albumin (table 1). ECG showed low voltage. The hemoglobin was 7.4 g per 100 ml,
erythrocyte sedimentation rate, 16 mm in 1 hr; white cells, 6900 per ,uliter with a normal differential count; thrombocytes, 265,000 per ,uliter; and eosinophiles, 44 per ,uliter. Serum iron was 140 ,ug per 100 ml; total iron-binding capacity, 206 ,ug/100 ml; and folic acid, 0.006 ,ug per ml. Serum proteins. Total protein was 4.07 g per 100 ml; albumin, 1.57 g per 100 ml; a,-g10bulin, 0.46 g per 100 ml; a2-g10bulin, 0.65 g per 100 ml; ,a-globulin, 0.57 g per 100 ml; and y-globulin, 0.82 g per 100 ml; prothrombin, 910/0; acetylcholinesterase, 0.59 ,umoles per min per ml (normal values, 3.2-5.7). Haptoglobin, fibrinogen, and ceruloplasmin were all normal. Immune electrophoresis showed the presence of all immune globulins, an increase of a2-macroglobulin and a decrease of transferrin, a glycoprotein, " and albumin. Hepatic function tests. Serum bilirubin, alkaline phosphatase, and thymol turbidity were normal. A hepatic biopsy revealed the presence of a considerable amount of hemosiderin in the liver cells, but was otherwise normal. Renal function. Serum creatinine and serum urea were normal. There was no protein, blood,
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CASE REPORTS
January 1966
or sugar in the urine, and the sediment was normal. Gastrointestinal function tests. These tests showed steatorrhea with a maximal fat excretion of 32.9 g per day. A Schilling test was abnormal both with and without added intrinsic factor (4.5 and 1.6%, respectively). Urinary 5 HIAA excretion was normal. Achlorhydria was present on augmented histamine test. Pancreatic function test (after Borgstrom') showed a slightly depressed function. Stool cultures revealed no tubercle bacilli or salmonella. Hormones and vitamins. Urinary excretion of 17 ketosteroids and 17 hydroxycorticosteroids was normal. Protein-bound iodine was slightly depressed (2.7 p.g per 100 ml). However, the concentration of diffusible thyroxine determined on a later occasion was normal. Thiamine tolerance test, serum ascorbic acid, and serum B12 all showed normal values. Radiological findings. Examination of the upper gastrointestinal tract revealed an extraordinary pattern with numerous, fine, polypoid filling defects in the stomach and duodenum (fig. 3) . No ulcer or tumor was seen. A barium enema similarly showed many defects in the entire colon. There were multiple polyps varying in size from 5 to 10 mm. The haustral folds were normal (fig. 4). A small intestinal series revealed coarsening of the mucosa. With the possible exception of the proximal jejunum (fig. 3), no alterations similar to those found in the stomach, duodenum, and colon were present. Cholecystography (fig. 4) and intravenous pyelography were normal. Sigmoidoscopy demonstrated multiple polyps and hypertrophy of the mucosal membrane. The lesions were more pronounced in' the sigmoid than in the rectum. A few punctate hemorrhages, but no ulcerations were seen. No rigidity was observed. A biopsy of a rectal polyp showed only cystlike dilations of several glands. A skin biopsy from a nonpigmented area was normal. From an area with hyperpigmentation a marked and regular accumulation of pigment was present in the basal epithelial layer. The pigment looked like melanin. An increased number of "clear cells" were also seen.
TABLE
1. Laboratory data before and following conservat1've treatment
I Hemoglobin (g/100 ml) Serum protein (g/100 ml) Serum albumin (g/100 ml) Serum sodium (meq/liter) Serum potassium (meq/liter) Serium calcium (mg/100 ml) Serum phosphorus (mg/100 ml) Serum magnesium (meq/liter) Stools (g/day) Fecal fat (g/day) Weight (kg)
October
1964, on
first admission
December 1964, after treatment
I
January 1965, on second admission
7.4
10.1
9.0
4.07
4.6
2.97
1.57
2.0
0.50
133
136
131
2.9
4.5
4,5
4.7
7.4
6.2
2.9
3.2
0.7
1.4
2000 45.7 52.7
600 51. 7
I
I
3,0 1.3 1300 74 57.2
Subsequent Course Initially, the patient received parenteral nutrition with fluid, electrolytes, fat emulsions, and amino acids. Since she was anemic and her stools gave a consistently positive benzidine re-
FIG. 3. Radiogram showing polypoid filling defects in the stomach and coarsening of the mucosa in the proximal jejunum. Mucosal prolapse is present in the pylorus.
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FIG. 4. Radiogram after barium enema. Numerous filling defects are present in the colon. Note the visualization of the gall bladder after a previous cholecystography. The gall bladder contains no polyps. action, transfusions of blood and plasma were given. No overt hemorrhage was present. Later she was placed on intensive substitution therapy including biweekly injections of calcium, magnesium, vitamins, and daily oral supplements of potassium (54 meq) , calcium (1150 mg), and vitamin D (2000 IU, later 300,000 IU). Opium was given daily to keep the number of movements to a minimum. A planned low fat diet had to be cancelled because of the patient's reluctance to change her dietary habits. In an attempt to eradicate a possible abnormal bacterial flora within the gastrointestinal tract she was unsuccessfully treated with tetracycline and a yogurt preparation. Since the radiological examinations and the gastrointestinal function tests revealed extensive lesions all through the alimentary tract, it was decided to perform a temporary ileostomy. By doing so it could be established whether the colon represented the major route of electrolyte and protein loss and, if so, a colectomy might be beneficial to the patient. However, shortly after the transfer to the surgical department the patient underwent a marked improvement which was reflected by the laboratory tests 7 weeks after admission (table 1).
Considering the fact that no radical treatment was possible, she was discharged on substitution therapy. The improvement was not of long duration. One month later she was readmitted, and from then on her condition rapidly deteriorated. Fecal fat was more than twice as high as on thEl first admission. Her serum albumin had dropped to a level of 0.50 g per 100 ml and edema of the legs and back was present (table 1). An emergency subtotal colectomy was performed at which time steroids were administered. The wall of the stomach was thick and edematous. When a small gastrotomy was made on the anterior wall of the antrum, a large number of fingerlike, \12- to 2-cm long polyps protruded through the opening. A biopsy showed polypoid tissue with a mucin-producing epithelium and a large number of grossly dilated glands in the stroma. The small intestine appeared grossly normal. On palpation, however, it was felt to be granular. A biopsy of the proximal jejunum and of the distal ileum revealed that the villi were blunted and sparse. No polyps in the strictest sense were seen. Surprisingly, microscopy showed a severely distorted structure of the mucosa.
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CASE REPORTS
111
FIG. 5. High power magnification of biopsy from the ileum. A single normal villus is present (X 210).
The villi were scanty and short and many cystlike glands were seen in the lamina propria (fig. 5). The resected colon was cut open longitudinally. The appearance of the mucosa was highly abnormal. The transverse folds were €xtremely hypertrophic, and at many places large numbers of small bluish polyps with a -diameter up to 2 cm were present (fig. 6). Again the microscopic picture was dominated by di1ated glands and cysts (fig. 7). Many of the cysts were filled with inspissated material. Similar, though much less pronounced Dhanges were present in the appendix. The liver, gall bladder, pancreas, and kidneys were found normal during the operation. The postoperative course was brief. For a few days her condition remained stable. Then she developed increasing gastric retention and signs of ileus. Re-exploration revealed no mechanical obstruction. She died rather suddenly from pulmonary embolism 7 days after the co1ectomy and 10 months after the onset of her disease. Autopsy revealed a fresh pulmonary embolism. In the esophagus a number of 1- to 2-mm broad mucosal prominences were present. No
other macroscopic lesions not already recognized during laparotomy were seen. On microscopy the liver displayed a fatty metamorphosis. The lamina propria of the jejunum contained an increased amount of fibroblasts and collagen fibers. Otherwise, nothing new was revealed. The esophagus appeared normal. The skin contained atrophic hair follicles .
Special Investigations Cr51-albumin. Crs1 -albumin (ca. 20 /Lc), prepared according to the method described by Waldmann,6 was injected intravenously during the first admission. The fecal excretion of Cr51 in a succeeding 4day period amounted to 5.5% of the injected dose (normal, less than 1%). Thus the test demonstrated an abnormal gastrointestinal plasma protein loss. Ji31- albumin study. This study was performed 1 week later with a preparation made after McFarlane's monoiodine chloride method. 7 Part of the injected dose (a total of ca. 50 /Lc) was inadvertently deposited in the subcutaneous tissue. Conse-
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CASE REPORTS
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FIG. 6. Colon after it was removed and cut open. Prominent hypertrophic folds and scatt ered polyps are present all through the specimen.
FIG. 7. Histological picture of a colonic polyp. The "cysts" contain a granular inspissated material.
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CASE REPORTS
January 1966 TABLE
2. Plasma protein turnover studies J13'-albumin
Observed value
Plasma volume (Ull) Serum concentration (g/ lOO ml) Intravascular mass (I.V.M.) % of total mass Fractional catabolic rate, % of I.V.M./ day Synthetic rate (g/day) Fecal excretion of the label , % of injected dose/ 4 days
1.86
Normal range
4.44-5.86
Observed value
Norm,l range
Observed value
Normal range
5.5
<1.0
2900 1890-3670 0.96 0.62-1.10 52.8 41-63
17.0
6-14
21.1
5.8- 7.4
9 .2 8 .8
8-15 <0.5
5.9 18.2
1.0-3.9 <0.5
quently it was not possible to calculate the pool distribution. However, the metabolic clearance could be established after the method of Pearson et al. 8 The P :H-albumin degradation rate amounted to 17.0% of the intravascular pool per day (r..ormal value, 6 to 14) (table 2). Assuming steady state conditions and an un denatured tracer substance, this figure indicated a synthetic rate -of 9.2 g per day or 0.19 g per day, which fell within normal range (0.16 to 0.24 g per kg per day). A remarkable feature was the large ~mount of label, 8.8% of the injected dose, -excreted in the stools in 4 days (normal figure, < 0.5%). J125- yG - globulin turnover. YG-Globulin was isolated on a diethylaminoethyl (DEAE) -column 9 and subsequently labeled with p25 after McFarlane. 7 Approximately 20 fJ-c were given intra-venously and the turnover calculated after Matthews. 10 The degradation rate (table 2) was 21.1 % of the intravascular pool per -day (normal values, 4.2 to 9.6).9 The synthetic rate was high, 5.9 g per day (normal, 1.0 to 3.9). The total y-globulin fraction as -determined by paper electrophoresis was applied in the calculation. The distribution ratio calculated according to Nosslin l l was 52.8; i.e. 52.8% of the total YG-globulin pool was located in the blood stream. This figure was normal (normal values, 41 to 63) . The fecal p25 excretion was 18.2% of the injected dose in 4 -days, an extremely high figure (normally Jess than 0.5%) .
Cr51 -albumin
JI2''YG_globulin
Paper electrophoresis of gastric secretion revealed the presence of small amounts of several protein fractions. The YG-globulin concentration determined immunochemically was about 0.3 g per 100 ml both in gastric secretion and in the stools. (Immunochemical determination of YG-globulin was performed by Dr. J ¢rgen Clausen, Institute of Biochemistry, Copenhagen.) Gastrointestinal Loss of Electrolytes Stomach. The samples aspirated during augmented histamine test were analyzed for electrolytes. The values of five individual collecting periods of 15 min were very similar. If recalculated as daily loss they amounted to 9 meq of potassium, 1.2 meq of magnesium, and 63 mg of calcium per 24 hr. This would presumably represent figures of maximal loss and did not indicate any appreciable loss of these electrolytes via the stomach. Intestine. Due to the patient's unstable condition it was impossible to perform proper balance studies. Several fecal analyses were made. On days with a large stool volume, as much as 3.80 g of calcium and 27 meq of magnesium were lost by this route as compared with an oral intake of 2.34 g of calcium (including 1.15 g in tablets) and 11.4 meq of magnesium. Discussion
Cronkhite and Canada 4 in 1955 reported two cases of diffuse gastrointestinal polyposis associated with alopecia, nail atrophy, and hyperpigmentation. A similar case was
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CASE REPORTS
published in 1961 by Kennedy and Hirson. 12 They described their patient as "a transient syndrome with Peutz-Jeghers features and ectodermal change." However, several features typical of PeutzJ eghers' syndrome were missing. The disease made a late debut, there was no family history, and no mucosal pigmentation. In fact, having skin, nail, and hair changes together with diffuse gastrointestinal polyposis, the patient displayed a typical Cronkhite-Canada's syndrome. Martini and Dolle 13 reported three cases of Menetrier's syndrome, a designation most often used synonymously with giant hypertrophic gastritis. One of the patients died. At autopsy diffuse polyposis was present in the stomach, small intestine, and the whole colon. In addition the patient had ectodermal lesions in the form of "mycosis" of finger- and toenails. Consequently, it was felt justified to include the case in the present survey. Johnston et al.H and Zdansky and Riederer 1:> each published a typical case. Thus, the present one seems to be the seventh. Table 3 compares clinical and radiological data in the seven reported cases. They were all middle-aged or elderly patients. Six were women. All except one (no. 6) had diarrhea, and in four it was the initial symptom, whereas a loss of taste was the first complaint in two. The course was fatal within a period of 6 to 18 months in five cases. They died in a state of severe cachexia. One patient (no. 3) was an extraordinary exception, because she underwent a complete remission within 2Y2 months. 12 Another case (no. 6), the only male,15 apparently underwent a complete recovery following right-sided hemicolectomy, which was performed as an emergency operation because of an intussusception. The roentgenograms revealed gross alterations compatible with extensive polyposis in the stomach and in the colon. In four cases (nos. 1, 3, 5, 6) polyps were suspected on the small intestine although no polyps in the strictest sense were present. In the esophagus a very limited number of small polyps were found in Case 3 (radiologically) and Case 7 (at autopsy).
Vol. 50, No.1
Laboratory data are depicted in table 3. Normal serum proteins were present in Case 3, in whom the syndrome was transitory, in five patients serum proteins were low, and in the remaining case (no. 1) serum protein values were not given. It was reported, however, that this patient gradually accumulated considerable edema of her legs. The hypoproteinemia in these patients was notably a hypoalbuminemia. Since hepatic function tests were normal and proteinuria was absent (case nos. 1-3,5,7), an underlying gastrointestinal protein loss seemed highly probable as suggested by Johnston et al.14 Martini and Dolle 13 demonstrated an abnormal fecal pS1_ polyvinylpyrrolidone excretion (3.28 % of the inj ected dose, normally less than 1%) in their case (no. 4) as evidence of an abnormal gastrointestinal protein loss. In the present case, Johnston's suggestion also proved to be correct as demonstrated by means of Cr51-albumin (table 2). In gastric aspirations during augmented histamine test no Cr51 was present. Therefore gastric protein loss was probably negligible, and the abnormal protein loss must have proceeded at a lower level of the alimentary tract. The fecal recovery of large amounts of radioactive iodine in the turnover studies with iodine-labeled albumin and YG-globulin was strong evidence that the colon represented the most important site of plasma protein loss.16 Actually, this finding underlay the rationale to perform a colectomy. Serum calcium and serum potassium were depressed in the four cases (nos. 2, 4, 5, 7, table 3) in whom they were determined, and in our case to such an extent that both muscular weakness and tetanic manifestations occurred. A pronounced hypomagnesemia was an associated phenomenon at least in our case. Her tetanic symptoms did not vanish until parenteral calcium therapy was supplemented with magnesium. It seems reasonable to assume that the electrolyte deficiencies were at least partially due to intestinal loss. Although no proper balance studies have been performed in any of these patients, a net loss
8
Generalized
Fatal
F,42 Diarrhea
2~2'
Spontaneous recovery
F,69 Anorexia, loss of taste 18
-------
3.3
6.4
6
M,54 Abdominal pains, nausea
Case 6
F,58 Loss of taste
Case 7
"Normal"
2.9
0.7
2.9
4.3
10 >6 Apparent recov- Fatal ery after hemicolectomy Stomach, ileum, Stomach, duo- Stomach, duodenum, jejudenum, colon, colon, rectum num, colon rectum 5.4 4.15 4.1 3.4 1.95 1.6 Fatal
2.0
8.5-->3.8
4.3 ca. 1.6
Stomach, colon
Fatal
2.6
"Normal"
Case 5
F,71 F,51 Edema of the Diarrhea, legs, diarrhea alopecia
Case 4
1.2
4.8
Stomach, duo- Generalized denum, colon, rectum 3.3 "Normal" 1.1 "Normal"
F,75 Diarrhea, transient pigmentation 9 yr before 17 Fatal
Case 3
a
Clinical and laboratory data: Cases 1 and 2, Cronkhite and Canada, 1955;4 Case 3, Kennedy and Hirson, 1961 ;12 Case 4, Martini and Dolle, 1961 ;1' Case 5, Johnston et a!., 1962;14 Case 6, Zdansky and Riederer, 1963;15 Case 7, Jarnum and Jensen (prc3ent case).
Serum protein (g/100 ml) Serum albumin (g/100 ml) Serum calcium (mg/lOO ml) Serum phosphorus (mg/ 100 ml) Serum magnesium (meq/ liter) Serum potassium (meq/ liter)
Radiological extension of polyposis
Duration (mo) Outcome
Sex, age Initial symptom
Case 2
3. Diffuse gastrointestinal polyposis with ectodermal changes (Cronkhite-Canada's syndrome)a
Case 1
TABLE
C,;(
.....
~
~
o
~
~ ~
~
'<::
....
£;
~.:
116
CASE REPORTS TABLE
Vol. 50, No.1
4. Gastrointestinal function tests
Schilling's test Case no.
Achlorhydria
With Without intrinsic intrinsic factor factor
Pancreatic function test
n-Xylose test
Glucose tolerance Steatorrhea t est
- - - - --
1 2
3
4 5 6
7
+
%
? Histamine-fast
Histamine-f ast Histamine-fast No + (Augmented histamine test)
gjday
g
%
Normal Flat curve Normal
Trypsin present in duodenal aspirate
I Normal 1.6
4.5
Slightly subnormal amylase concentrations In duodenal aspirates
of 1.5 g of calcium and 16 meq of magnesium was found in the feces of the present case on a day with a large, but not exceptional stool volume.
Gastrointestinal Function Tests Achlorhydria was present in at least five patients (table 4). Few absorption studies were made. Steatorrhea was present in one case (no. 7), absent in another (no. 5), and not mentioned in the remaining five cases. Also, the glucose tolerance test was normal in some and abnormal in others. An-xylose test was highly abnormal in the present case as was a B12 absorption test both with and without added intrinsic factor. Altogether, there could hardly be any doubt that malabsorption was more pronounced in the present case than in the others. It agreed well with the severe histopathological lesions found in the small intestinal mucosa (fig. 5). Pancreatic function was essentially unchanged in the two cases examined (nos. 3 and 7). Pathological Lesions In the present case gross macroscopic alterations were present in the stomach (numerous large polyps) and in the colon (tremendous hypertrophy of the transverse folds with scattered polyps), whereas the small intestine did not present any polypoid
1.6
Flat curve
No
45.7
lesions, although a marked villous atrophy was evident through a magnifying glass. Quite contrary to the macroscopic picture, the histological lesions were surprisingly uniform throughout the gastrointestinal tract. An intact epithelium, tortuous glands, and cysts of varying size occurred at all sites. In the colon the cysts often contained a granular material suggesting the presence of protein. At autopsy of Case 4 an almost identical histological picture was found all through the gastrointestinal tract. 13 Also in Case 5 a similar picture was seen in a rectal polyp.14 Cronkhite and Canada reported that in Case 1 "the lesions in the gastrointestinal tract were consistent with simple adenomatous polyps" (autopsy finding), and in Case 2 a biopsy from a sigmoid polyp showed a benign adenomatous polyp. In no instance was there any evidence of malignancy, lymphatic involvement or inflammatory process; i.e. lesions which most often underlie an abnormal gastrointestinal protein loss.
Etiolgoy The etiology of Cronkhite-Canada's syndrome remains obscure. The fact that the syndrome in one case,12 although fully developed, underwent a complete remission, suggests that exogenous agents may be involved. Also, there seemed to exist no hereditary basis in any of the cases. In this
CASE REPORTS
January 1966
117
respect, the syndrome deviates from other and at autopsy. The macroscopic picture .syndromes of gastrointestinal polyposis as- was different at various sites (polyps in the sociated with ectodermal changes, e.g. 'stomach, villous atrophy in the small inPeutz-Jeghers' syndrome with small in- testine, hypertrophic rugae with scattered testinal polyposis and mucocutaneous polyps in the colon). In contrast, the mifrecklelike pigmentation2 , 3 and Gardner's croscopic picture was highly uniform and .syndrome with nondiffuse colonic polyposis characterized by cystlike dilations of the glands. and epidermoid cystS. 17 The ectodermal changes were nonspeThe etiology of the syndrome remains ·cific in the sense that each component obscure. The ectodermal changes seem to could be referred to some biochemical de- be an inherent part of the syndrome and rangement or nutritional deficiency state not secondary to malabsorption. due to malabsorption. Hyperpigmentation is a symptom in pellagra, and hair and nail REFERENCES changes may occur in states of prolonged 1. Menetrier, O. 1888. Des polyadenomes gastrihypocalcemia and-in animal experiments ques et de leurs rapport avec Ie cancer de -hypomagnesemia. l'estomac. Arch. Physiol. Norm. Path 1: However, it is improbable that this was 32-55. the mechanism in the patients. First, one 2. Peutz, J. C. A. 1921. Over een zeer merkpatient with transitory lesions 12 had norwaardige, gecombineerde familiaire polymal serum electrolyte values and no malabposis van de slijmvliezen van den Tractus sorption. Second, steatorrhea was also intestinalis met die van N eusheelholte en tLbsent in Case 5 (table 4). 8 Thirdly, the gepaard met eigenaardige pigmentalies van hind.-en slijmvliezen. Nederl. Maandschr. ectodermal changes developed at such an G2neesk. 10: 134-146 . .early stage compared to other malabsorp3. Jeghers, H., V. A. McKusick, and K. H. tive manifestations that a true deficiency Katz. 1949. Generalized intestinal polystate could hardly exist at the time when posis and melanin spots of oral mucosa, they made their appearance. Therefore, it lips and digits; syndrome of diagnostic is reasonable to conceive that the ectodersignificance. New Eng. J. Med. 241: 993mal changes were an inherent part of the 1005. syndrome. 4. Cronkhite, L. W., and ,Yo J. Canada. 1955. Summary
A case of Cronkhite-Canada's syndrome is presented. The syndrome, which is extremely rare, is characterized by diffuse gastrointestinal polyposis, alopecia, nail atrophy, and hyperpigmentation of the skin. Severe malabsorption, hypoproteinemia, and marked depression of serum calcium, magnesium, and potassium were additional features. It could be shown by means of labeled proteins that large amounts of albumin and I'G-globulin leaked into the intestinal tract and, in particular, into the colon, whereas gastric protein loss was negligible. Also, although no proper balance studies could be carried out, evidence of an intestinal net loss of electrolytes was present. Severe lesions of the entire gastrointestinal tract were found during laparotomy
5.
6.
7.
8.
9.
Generalized gastrointestinal polyposis. An unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. New Eng. J. Med. 252: 1011-1015. Borgstriim, B., A. Dahlqvist, G. Lundh, and J. Sjiivall. 1957. Studies of intestinal digestion and absorption in the human. J. Clin. Invest. 36: 1521-1536. Waldmann, T. A. 1964. The preparation of chromium51 labelled albumin. Panel on radioisotope techniques in the study of protein metabolism. 1. A. E. A. Vienna, June 1964. McFarlane, A. S. 1958. Efficient trace-labelling of proteins with iodine. Nature (London) 53: 182-183. Pearson, J. D., N. Veall, and H. Vetter. 1958. A practical method for plasma albumin turnover studies. Radioakt. Isotope Klin. Forsch. 3: 290-297. Andersen, S. B. 1964. Metabolism of human gamma globulin (gammass-globulin), p. 31. Blackwell Scientific Publications, Oxford.
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CASE REPORTS
10. Matthews, C. M. E. 1957. The theory of tracer
experiments with Pal-labelled plasma proteins. Phys. Med. Biol. 2: 36--53. 11. Nosslin, B. Cited in ref. 9, p. 115. 12. Kennedy, J. A., and C. Hirson. 1961. A transient syndrome with Peutz-Jeghers features and ectodermal change . Proc. Roy. Soc. Med. 54: 234-235. 13. Martini, G. A., and W. Dolle. 1961. Menetrier-Syndrom. Polyadenomatosis des Magens mit Eiweissverlust in den MagenDarm-Kanal. Deutsch. Med. Wschr. 86: 2524-2530. 14. Johnston, M. M., J. W. Vosburgh, A. T. Wiens, and G. C. Walsh. 1962. Gastrointes-
Vol . 50, No . 1
tinal polyposis associated with alopecia, pigmentation and atrophy of the fingernails and toenails. Ann. Intern. Med. 56: 935-940. 15. Zdansky, E., and J. Riederer. 1963. Gastro-
intestinale polypose Adenomatose mit Hypoproteiniimie und ektodermalen Storungen. Radiol. Clin. (Basal) 32: 254-263. 16. Jarnum, S. 1961. Fecal P'l1- output after intravenous injection of I131-labelled human serum albumin in normo- and hypoproteinemic subjects. Scand. J. Clin. Lab. Invest. 13 : 462--475. 17. Gardner, C. McG. 1948. Polyposis of the colon. Arch. Surg. (Chicago) 56: 75-78.