Diarrhea associated with adrenal ganglioneuroma

Diarrhea

Associated

with Adrenal

Ganglioneuroma* New Findings Related to the Pathogenesis of Diarrhea J.

RICHARD

HAMILTON,

(c)t, INGEBORC C. RADDE, and GORDON JOHNSON, PH.D.

M.D., F.R.C.P.

Toronto,

M.D., PH.D.,

F.K.c:.P.

(c)

Ontario

A three year old boy was studied for six months preoperatively and then after resection of a functioning ganglioneuroma. The predominant clinical features were long-standing massive watery diarrhea and profound muscle weakness. Studies of intestinal function prior to resection indicated a derangement of the function of the small intestine with massive fecal excretion of water and sodium. Malabsorption of vitamin Brz suggested an abnormality in the function of the distal ileum. Initial determinations of urinary 3-methoxy-4-hydroxy mandelic acid (VMA) excretion showed normal or slightly increased quantities. However, urinary norepinephrine excretion was excessive and epinephrine was undetectable in all but one of several preoperative urine specimens. Diarrhea was unrelated to deficiencies of potassium, folic acid and vitamin B12. Altered intestinal motility probably was not the mechanism by which intestinal function was altered. The hypothesis is suggested that the derangements of intestinal function arise as a result of altered intestinal blood flow in response to an abnormal pattern of catecholamine secretion.

A

N association between tumors of the neural crest and chronic diarrhea has been described frequently in children [ 7-81. Although the emergence of methods for the measurement of urinary catecholamines and catecholamine metabolites in recent years has provided valuable new technics for the diagnosis of these functioning tumors [g-13], the pathogenesis of the associated diarrhea remains an intriguing mystery. A further case in a three year old boy will be described because comprehensive studies of the child’s intestinal function and catecholamine excretion carried out before and after resection of a right adrenal ganglioneuroma have suggested promising new avenues for the investigation of the pathogenesis of diarrhea in this disorder. The case is of interest from a diagnostic standpoint also, since initially the typical biochemical and roentgenologic features were not evident.

CASE REPORT

A boy was transferred to The Hospital for Sick Children, Toronto, in September 1965 at the age of two years, six months. Born at thirty-six weeks’ gestation with a birth weight of 2.1 kg., he progressed satisfactorily until the age of eight months. At that time, severe watery diarrhea developed suddenly and persisted for the next two and a half years. During the year prior to his admission weight gain was inadequate, but he remained generally well with a good appetite. He was free of pain with no vomiting or apparent blood loss. Investigations in St. Joseph’s Hospital, Hamilton, Ontario, had revealed a persistent hypokalemia but no specific cause for the diarrhea. The removal of gluten, milk or fat from the diet had no effect on his condition. The child appeared chronically ill (Fig. I). His height was at the twenty-fifth percentile, his weight below the third. He had a smooth tongue. No abnormal abdominal mass was palpable, even when he was examined under general anesthesia. Bowel sounds

* From Departments of Pediatrics and Pharmacology, University of Toronto, and The Clinical Investigation Unit, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. This study was supported by grants from the Medical Research Council of Canada and the Ontario Cancer Research and Treatment Foundation. Manuscript received March 27, 1967. t Ciba Medical Research Fellow, 1965-1966. VOL.

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453

454

Diarrhea

and Adrenal

Ganglioneuroma-Hamilton

et al.

FIG. 1. The patient on admission (left) and six months after the resection of an adrenal ganglioneuroma (right). Note marked improvement in muscular development. were normal and moderate gaseous distention was noted intermittently, Blood pressure was 95j50 mm. Hg and remained normal on repeated measurements over the next six months. Wasting and weakness of the skeletal muscles, particularly those of the proximal groups in the legs, was striking and caused the child to walk with a bizarre waddling gait. At no time was abnormal flushing or sweating observed. During the next six months, most of which were spent in the hospital, he continued to have diarrhea, at times passing more than 1 L. of watery stool in a day. Stools were always alkaline and contained no sugar, pus cells or blood. The diagnoses of the usual causes of chronic diarrhea in childhood were excluded by appropriate studies. Neither pathogenic bacteria nor parasites were found on repeated examinations of stool and duodenal juice. Sigmoidoscopic examination was within normal limits. Biopsy specimens of mucosa of the rectum and distal duodenum revealed no abnormality on light microscopy. The chloride content of sweat was 26.3 mEq. per L. Renal concentrating power was impaired (maximal urinary osmolarity 663 mosm. per L.). Repeat routine urinalyses were within normal limits. On March 30, 1966, approximately six months after the child’s first admission, laparotomy was carried out by Dr. B. F. Shandling. The gastrointestinal tract was examined carefully and no abnormality was found. A tumor involving the right adrenal gland was identified and resected completely. It was approximately 6 cm. in diameter, hard and encapsulated. Histologic studies of tissue from several areas of the

tumor showed the features of a benign ganglioneuroma with small calcium deposits and remnants of normal adrenal cortex adjacent to some areas. Postoperatively, diarrhea ceased immediately. Muscle tone and bulk improved rapidly and the child exhibited a normal gait within a month of surgery. When last seen, nine months after surgery, he was in excellent health with no diarrhea (Fig. 1). METHODS

The patient was studied in a clinical investigation unit in which conditions permitted close control of dietary intake and precise collections of urine and stool. Urine specimens for catecholamine and catecholamine metabolite determinations were collected on ice in vessels containing 25 ml. 6N hydrochloric acid and frozen until assayed. For the assay of 3-methoxy-4hydroxymandelic acid (VMA) the method of Sunderman et al. (74) was used, for homovanillic acid (HVA) * the method of Williams and Greer [ 751 and for norepinephrine and epinephrine that of Euler and Lishajko [76]. Tumor tissue was homogenized in 5 per cent trichloroacetic acid shortly after resection and stored frozen until catecholamine levels were determined [ 761. Fecal fat was assayed on pooled collections of five days’ duration [77]. Dietary intake was calculated from the weight of food offered and that rejected. Fat excretion was expressed as a percentage of dietary * Bio-Science AMERICAN

Laboratories, JOURNAL

Los Angeles, OF

California. MEDICINE

I diarrhea

and lIdrena

Ganglioneurolna

Il/n/il/c,r/

1; 5

r/ N/.

--3-Methoxy-4-IHydrosymandelic acid IVM.\) (mg./24 hr.)

I )ate

1 lomovanillic .\cid (HV 1) (mg./24 hr. I

iYorepinephriw (/q/24 hr.)

I:pincphrinr I *p. 24 h!-.

I

ivorma1VdUPJ 1.5-3.6

<2.5*

0.2~16

4t

0.x

‘J li

Patimt (Preoperatiw rh9j lo ,/65

1.3

1.5

14.9

,I

26.7

0

2.3

23.9 34.3

0 (1 0

12165

1.7

15.7

(1

2166

6.9 3.9 4.1 3.4

1 l/65

3/66

Patient (Postoperatiz’e Values) 4/M

0.5 (24 hr. postop.) 0.2 0.9

(48 (72

12/66

* Data of t Data of

Clark et al. [ 731. Voorhess and Gardner

hr. postop.) hr. postop.) 3 .o

sodium. potassium, calcium and magnesium determinations [2_5,26]. Intestinal absorption of vitamin Blz was assessed by measuring the twenty-four hour urinary excretion of :TCo after an oral dose of the labeled vitamin using a “flushing” dose of parenterally administered vitamin B12 11.000 pg.). The test was then repeated with the additional administration of intrinsic factor. Isolated rabbit ileum peristalsis was studied in nitro. Segments of intestine 3 cm. in length were placed in oxygenated Tyrode’s solution (25 ml.) and kept at 37”~. ‘l‘he bowel was suspended between two small hooks. the lower hook fixed and the upper attached by a thread to a transducer. A graphic recording of the longitudinal contractions of the bowel could then be obtained on a moving chart. Fresh fasting serum and hrparinized plasma from the patient and a con-

“(,I..

44,

Laboratories, MARCH

1968

28 0 4 1.2

2:9

[ 121, four normal children age fourteen months to three and half years.

intake. Measurements of urinary n-xylose excretion were based on five hour urine collections after an oral ,dose of 5 gm. [ 781.Blood sugar levels were measured by the method of Hoffman [ 791 adapted to the autoanalyser. \Xtamin A tolerance [XI], serum iron [Zi’] and serum vitamin B,?* [22] were measured by technics previously described. Formiminoglutamic acid (FIGLL) in urine was measured following an oral load of histidine [23,2i1]. Measurements of sodium, potassium and magnesium in stool and urine were made on seventy-two hour pooled collections. Duplicate diets were analysed over the same period. Flame photometry was used for

* &o-Science

5.2 4.2 22

Los Angeles,

California.

trol subject (a three year old of the same weight wit11 proved celiac disease but without diarrfkea) were added in increments to a total of 5 ml. to the medium and two minutes allowed for an effect. The experiment was undertaken in October 1965 and repeated in December 196.5. RESULTS

Catecholamine Studies. Results of tiriuary catecholarnine determinations during the preoperative and postoperative periods are summarized in Table I. Urinary levels of VMA were normal during the earIy phase of the investigation, at a time when the child had been symptomatic for nearly two years. Urinar), HVA was considered to be normal at that time also. In February 1966, five months later, VMA excretion had risen to 6.9 mg. per twentyfour hours. However, at that time the child was receiving prednisone therapy. Subsequent determinations with the child no longer on prednisone therapy remained slightly elevated. Postoperatively VMA excretion fell to low levels in the first twenty-follr hours and remained within normal limits. Analysis of urinary norepinephrine and epinephrine excretion, undertaken on stored frozen urine after the diagnosis was established, revealed increased excretion of norepinephrine

Diarrhea

456

and Adrenal LABORATORY

Ganglioneuroma-Hamilton

TABLE DATA-SMALL

et al.

II INTESTINAL FUNCTION

Patient

Preoperative

Normal Values

Data Fecal fat excretion, 5 day mean (% ingested fat) Vitamin A tolerance (maximal rise, rg. %) D-Xylose excretion (5 hr. urine, % of dose) Glucose tolerance (maximal rise, 1 hr. mg./lOO ml.) Serum proteins (gm./lOO ml.) Albumin Globulin Alpha, Alpha, Beta Gamma Serum iron, fasting (fig./100 ml.) Serum vitamin Bl2 (/.+g./lOO ml.) Schilling test (67Co) (24 hr. urine, y0 of dose) Without intrinsic factor With intrinsic factor Urinary FIGLU (5 hr. urine-mM/ hour)

lo/65

2166

5.2

3.1

12/66

>50

239

>15

14

14

18

>40

31,51

34

64

3.3-5.8 0.1-0.3 0.4-1.0 0.3-l .2 0.4-1.4

4.8 0.2 0.8 0.9 0.8

4.9 0.1 0.8 1.1 0.7

4.8 0.2 0.8 1.0 0.9

4.6 0.2 0.8 0.9 0.8

>50 44-212

85 52

, .

20 282

..

2 4

>lO% 4.1-10.3

Stool

10/20-23/65 3/11-14/66 3/18-21/66

65.2 44.8 31.6

3.1 12.1 0.2

56.9 32.4 37.3

4/16-19/66

30.1

25.4

0.9

ii2 30

. . .

.

Gastrointestinal Function. The patient’s clinical status with loss of weight, muscle wasting and severe diarrhea suggested a derangement of intestinal absorptive function. The pertinent laboratory data are summarized in Table II. Significant steatorrhea could not be demonstrated. No consistent abnormalities in glucose tolerance, vitamin A tolerance or xylose

DATA

hr.) Magnesium (mEq./24

Intake

output Urine

80

3.4

..

Potassium (mEq./24

Diet

4.4 0.2 0.7 0.8 0.8

. .

32

hr.)

4.2 524

TABLE III ELECTROLYTE BALANCE

Date

3/66

5

with virtual absence of epinephrine from all but one of the preoperative specimens. Immediately postoperatively the ratio of these compounds reverted to normal. Analysis of the tumor tissue showed a relatively high level of norepinephrine, 4.8 pg. per mg. of tissue compared with that of epinephrine, 1.7 pg. per mg.

Intake

Values

11/65


>lO%

Sodium (mEq./24

Postoperative Values

Diet

Supplement

output

Intake

hr.)

output

Urine

Stool

Diet

Urine

Stool

1.6 10.2 1.1

44.0 50.5 32.2

15.1 11.2 10.4

2.1 3.2 1.1

9.0 7.3 4.4

34.9

2.6

10.7

2.2

4.2

Preoperative Values 73.3 47.3 42.4

0 20.0 0

Postoperative Values 40.7

0

AMERICAN

JOURNAL

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725-

-

and

Oral I Potarslum

Adrenal

2o

Ganglioneuronm

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4 Time

Weeks

16

12 after

20

-Ikimiltm

r T 28 1

24

4.57

pi ni.

I 32

36

SURGERY

AdmIssion

FIG. 2. Serial determinations of the plasma concentrations of sodium, potassium and chloride with plasma pH and carbon dioxide content during the preoperative investigation and immediately postoperatively demonstrating a transitory rise of serum potassium in response to oral potassium therapy.

excretion were noted. Serum protein levels were repeatedly normal. During the course of investigations a mild iron deficiency anemia developed associated with a decrease in serum iron to 20 pg. per 100 ml. Tliere was no evidence of intestinal blood loss, and the hemoglobin returned rapidly to a normal level with oral ferrous sulfate therapy. The bone marrow was norinal. The initial serum vitamin Br2 concentration was low (52 pg. per cent). A Schilling test showed a marked depression of urinary excretion of “7Co (2 per cent) which was not corrected by the administration of intrinsic factor. Postoperatively, 30 per cent of an oral dose was excreted without the adniinistration of intrinsic factor. Initially urinary FIGLU excretion was elevated but the abnormality was corrected by the oral adniinistration of folic acid. Two overnight total twelve hour collections of gastric secretions were undertaken yielding 110 ml. and 96 ml. of juice. Neither specimen contained titratable acid. Histamine stimulation was not undertaken. Serial determinations of sodium, Electrolytes. chloride and pH in plasma are potassium, vo,.

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plotted in Figure 2. The most noteworthy finding was the marked initial hypokalemia which responded temporarily to oral potassiuiu supplements. Plasma sodiuin concentrations tended to be low also and the child was often iii mild acidosis. Data for sodium and potassium intake and excretion are shown in Table III and demonstrate the massive losses of both these cations from the intestinal tract prior to siqery.

3. Serial determinations of the serum concentrations of calcium, phosphorus and alkaline phosphatase in response to vitamin D preoperatively and postoperatively. FIG.

458

Diarrhea

and Adrenal

FIG. 4. Barium enema showing generalized of the colon prior to evacuation.

Ganglioneuroma-Hamilton

dilatation

Potassium supplementation raised the serum level and increased urinary excretion but also increased fecal losses. Postoperatively fecal losses decreased markedly and urinary excretion increased. Preoperative data for magnesium intake and excretion were normal (Table III). Serum levels of calcium and phosphorus were consistently within or near normal limits, as was serum magnesium (Fig. 3). Serum alkaline phosphatase rose to 66.5 King-Armstrong units

FIG. 5. The vascular supply to both kidneys and suprarenal areas was normal as outlined by aortography (March 1966). The right kidney outline is lower than that of the left.

et al.

during the child’s first month in the hospital and fell to normal after vitamin D therapy (400 units per day) was begun (Fig. 4). At no time was there roentgenologic evidence of rachitic changes in the bones. Results of liver function tests were normal. Roentgenologic Assessment. Roentgenograms of the small intestine taken after the ingestion of colloidal barium failed to show any significant abnormality. Since the absorptive data suggested a problem in the distal small bowel, the ileum was intubated and viewed under cinCradiography after the injection of colloidal barium. No abnormality of structure or motility was noted. The barium enema was of interest since the colon appeared distended and atonic (Fig. 4) and it emptied rather slowly. Plain films of the abdomen repeatedly failed to demonstrate abnormal intra-abdominal calcification. Intravenous pylography showed normal renal shadows with no changes in the the left kidney was upper poles, although slightly lower than the right. Tomography was used, combined with a rapid intravenous injection of dye but no further abnormality was seen. Aortography, undertaken shortly before surgery, and five months after pyelography, failed to demonstrate an abnormality in the blood supply to the adrenal glands (Fig. 5). In retrospect, however, it was realized that by that time the right kidney was displaced downwards in relation to the left when compared with the earlier pyelogram. Response to Medical Treatment. Before the diagnosis was eventually established at laparotomy, trials of medical therapy were undertaken, employing several oral medications which were added to the regimen singly and usually at intervals of at least a week. The patient’s response was evaluated by assessment of his general status and by measurements of fecal volume (Fig. 6). Potassium supplements given as either the chloride or gluconate salt had no beneficial effect on diarrhea although the serum potassium level did return to normal temporarily. Vitamin supplements including folic acid and a large parenteral dose of vitamin Blz produced no improvement. Fecal volume decreased on diphenoxylate hydrochloride (Lomotil@) but over a two week period, the child’s general condition was unchanged. The oral administration of tetracycline, 250 mg. per day, was discontinued after three days because of worsening of the diarrhea, the fecal AMERICAN

JOURNAL

OF

MEDICINE

~ecol

volume (ml /?A

Folic

3 day hr.)

Acid

meqn

mg,

Potassium

n1

mEq.

Diphenoxylats

HCI.

Tetracycline

ozzzzz

r^r330-

‘_120? mg.

mg.

Prsdnisone

20-

=x5 2250

mg.

30r0:10-

1:rc. 6. Fecal volume in response to a number of thrrapcutic after resection of the tumor. TOTAL

SERUM

ADDED

TO

VOLUME PATIENT

CONTROL

INCUBATION

MEDIUM

agents before surg-cry and

(ml.1

Tams in seconds

’

0

I

30

, 60

I

90

FIG. 7. Representative segments of tracings of longitudinal contractions of guinea pig ileum studied in Ctro (oxygenated Tyrode’s solution at 37”c., 25 ml.). AIthough the patient’s serum produced increased amplitude of contraction when added in sufficient quantity (5 ml.), the response did not differ from that observed using strum from a control subject.

volu~rre increasing to 1,300 1111.per day. PredniSOIIC was given and the child’s initial response was encouraging with ilnprovement in general status, a weight gain of 2 kg., a change to semiformed stools and a decrease in fecal volume. However, the effect did not persist and after six weeks diarrhea recurred. By this time the child delllonstrated clinical features of hyperadrenocorticism although he was not hypertensive. The dose of adrenal steroid was then decreased gradtlally and discontinued. VU,..

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1968

In lrtro ,Ytudies. The response of isolated rabbit ileum to seruul from the patient and frown a control subject assessed on two occasions is shown in representative tracings of peristaltic waves in Figure 7. The amplitude of contraction increased slightly with the addition of a total of 5 ml. of the patient’s serum to 25 1111.of the medium, but the salne results were obtained using control serum. The responses to plasrua from the patient and the control were identical to those obtained rising serulu.

460

Diarrhea

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Ganglioneuroma-Hamilton

COMMENTS

There is no doubt that in our patient diarrhea was directly related to the presence of an adrenal ganglioneuroma. The clinical picture was similar to that of cases previously recorded [7,3,5-g], and cessation of diarrhea after the tumor was resected was immediate and evidently permanent. Since the tumor did not involve the bowel either directly or by extrinsic pressure from the tumor mass, the observed alterations in intestinal function were probably related to some function of the tumor. Neural crest tumors are known to exhibit abnormal patterns of catecholamine metabolism and, in patients, to produce abnormal excretion patterns of these pharmacologically active substances [4,70]. However, only a minority of patients with such tumors manifest diarrhea [2,27] and in these patients a distinctive abnormality of metabolism of the known catecholamines has not been described. In the present study the problem of the pathogenesis of diarrhea due to neural crest tumors was approached in two ways, first by attempting to define the specific defects in gastrointestinal function in the patient and then by assessing the various ways in which such an effect might be mediated. Our patient did have specific defects in intestinal function, the most striking of which was the massive fluid volume of his stool. This loss of water was undoubtedly related to the high fecal output of sodium and was accompanied by excretion of large amounts of potassium. These losses probably represent a defect in intestinal absorption of sodium, with a consequent impairment of water transport [28]. No neoplastic or inflammatory lesion was found that might have produced excessive excretion of these substances into the intestinal lumen. In man the major site of sodium and water absorption is the small intestine [29]. Whether rates of absorption are greater in the proximal or the distal portion of the small bowel is controversial [30,37 ]. The exact relationship of excessive fecal losses of potassium to defective sodium and water transport is obscure. The findings of a low level of vitamin Biz in the patient’s serum and, subsequently, defective absorption of the vitamin not corrected by intrinsic factor have not been reported previously. They suggest a defect in the distal portion of the small intestine since this region is the normal site of absorption of vitamin Brz in man [32]. Studies in sheep indicate that the ileum may also be the site of magnesium

et al.

absorption [33] and in the human subject extensive resection of the ileum can lead to steatorrhea and magnesium deficiency, although it has been suggested that excessive fecal losses of magnesium are consequent to steatorrhea in such cases [34, 351. Mild steatorrhea has been associated with a functioning ganglioneuroma [ 71. In our patient both fat and magnesium were absorbed normally, indicating that some aspects of ileal function were preserved. The patient’s quick response to oral iron therapy, the normal excretion of xylose and the normal glucose tolerance tend to rule out a serious impairment of function of the duodenum and upper jejunum [29,36,37]. The only evidence for impaired colonic function comes from the unusual barium enema. This examination has been recorded as normal in two previous case reports [ 7,3]. Several mechanisms might account for the colonic distention in our patient, the massive volume of stool reaching the colon, secondary potassium deficiency or a primary effect of the tumor itself on the large bowel or its sphincters. A similar abnormality may occur in some (but not all) patients with diarrhea and hypokalemia due to islet cell tumors [38]. The cause of the colonic abnormality can only be speculated upon but the barium enema may be a diagnostic aid. Having suggested that the most significant abnormality of intestinal function lies in the small bowel, and perhaps more particularly in its distal portion, the question arises as to how such an effect might be mediated. The lack of response to therapeutic trials of oral supplements of potassium, folic acid and then parenterally administered vitamin B1, indicates that these secondary deficiency states were not factors of significance in the causation of diarrhea. Stickler et al. [5] were unable to demonstrate any beneficial effect of parenteral potassium therapy on diarrhea in their case. The response of our patient to prednisone therapy is difficult to interpret, since after what seemed to be a significant improvement initially his condition deteriorated while receiving the drug. A favourable response to prednisone therapy has been reported in a similar case [5]. Perhaps adrenal corticoid enhanced sodium and water absorption in the small intestine of these children. In the adrenalectomized rat, intestinal absorption of water is impaired [39]. Watery diarrhea and malabsorption occur in Addison’s disease [40,47]. It is probable that the effect of neural crest tumors on the intestinal tract is mediated by AMERICAN

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I)iarrhea

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C;angliolleul.olna---I-lomilti/,,

solnc abnorliiality of catecholamine secretion. The present case is the first such case with diarrh(aa alld norinal lirinary excretion of VMA [ 1..3\. However, this particular catecholaruine Illc>tal,olitc is inactive biologically [42] and only A sIllal proportion of patients with ganglioneurolllas who excrctc excessive quantities of \-XV. have diarrhea [2,3]. Xot all patients with gallglic,nenromas, on the other hand, excrete tsxccssi\ e anlounts of VMA I, 1,?]. -411intriguing obsrr\ation frown the present study is that of excessi\-e urinary excretion of norepinephrine, \lith absence of epinephrine in all but one specimm. Furthermore, epinephrine appeared in the urine illlmediately after the tumor was resected. The ttllnor must have suppressed the excretion, and presunlably the secretion of epinephrine from the patient‘s one normal adrenal gland. It is possible, therefore, that a deficiency rather than an excess of a particular catecholamine or catecholamine metabolite leads to impaired intestinal function and diarrhea. In certain patients with pheochromocytoma a similar excess of norepinephrine with concomitant suppression of epinephrine excretion has been observed [43, 4~1. IHowe\,cr, these patients have not had diarrhea, suggesting that it is not the suppression of epinephrine itself that accounts for diarrhea. .4bnormal catecholamine secretion, either excess of solne metabolite or, as we have suggested, possible suppression of some other metabolite could alter intestinal function by one or several different mechanisms. The mechanism most frequently discussed in this regard is that of altered motility. Bennett and Whitney [45] have studied pharlnacologic response of strips of human intestinal lnuscle in vitro to a number of agents. Epinephrine and norepinephrine consistently caused relaxation of muscle strips. iYo abnormality of intestinal motility could be detected in our patiellt. Pllthough sophisticated technics for motility measurements could not be applied to a small child, CinCradiographic visualization of colloidal barium injected into the ileum showed no abnormality. Furthermore, no factor could be demonstrated in the patient’s plasma or serum that altered intestinal contraction in z&o. Stickler et al. [S] obtained similar negative results in isolated segments of guinea pig ileum using a patient’s urine. Because of the lability of most catecholamines when assessed in vitro, such studies must be interpreted with caution. TWO further mechanisms are worthy of consideration. In the experimental animal, DuPont ““1..

44,

MARCH

1968

/‘t (11.

i(i 1

et al. [dd] ha\,e obscr\red delay-et1 mi~r;ltiotl of intestinal ~nucosal epithelial cells after i I III I IWIOsyrnpathectollly. Although in their short-term study structural changes were not appart~~t, in our patient, ill for Illore than tMo \‘cars; sollle abnorlnality of tllucosal structure ~t~oirlcl have been observed, had epithelial cell tllrno\.er t)c,cn deranged. In fact, the structure of illijcosa obtained froltl ollr patient’s distal duotic~lu~~~ was normal. Perhaps of Iiiore pertinerlce 10 our case, and yet flirther in the realm of speclllation, is the possible influence of abnormal catccholamine secretion on the blood flow to the intcstille and, more particularly, to its absorptive uLucosa. Epinephrine and norepinephrine ca\Ise vasoconstriction of the blood vessels of the illtcstinal nluscle and nlucosa of the experiIncnta1 aninial [47,48]. Epinephrine allay decrease bloocl flow to isolated segnlents of dog jejunum [&]. Csillg nlicrospheres. Peters and Womack [:%I have shown dilatation of mucosal artcrio~enous anastomoses of the stomach after the adrllillistration of epinephrine. The recent studies of M’inne et al. [51] suggest that transfer of watrr into the intestinal lumen varies directly with the blood volume passing through the intestinal \,asclllatllre. They found that norepinephrinc: reduced intestinal blood flow in the rat. Unfortlutatcly, technics suitable for the assessment of intestinal mucosal blood flow in a child are not a\,ailable and the influence of changes in blood flow on various paraineters of rnucosal function is not completely understood. [,57]. Acknowledgment: A large medical teal11 was involved in the study and treatment of this child. For assistance and advice we are indebted to Drs. B. .I. Reilly, C. F. Moes, G. F. C:ollins, M. J. Lynch, Leslie Organ and Gilbert Hill, the nurses and nutritionists of the Clinical Investigation Unit, Hospital for Sick Children and to Dr. .4. G. Hart, who suggested the correct diagnosis at the time he originally referred the child to our hospital. We are indebted, too, to the patient and his parents for their patience and cooperation. REFERENCES 1.

C. M. Ganglioneuroma as a cause of diarrhoea and failure to thrive.

SINDHU,

S.

and

ANDERSON,

Australian Paediot. J., 1: 56, 1965.

J. P. and KOOP, C. E. Ganglioneuromas in children. Surg. Gynec.& Obst., 121: 803, 1965. 3. ROSENSTEIN, J. B. and ENGLEMAN, K. Diarrhra in a

2.

HAMILTON,

child with a catecholamine-secreting neuroma J Pediat., 63: 217, 1963.

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and Adrenal

Ganglioneuroma-Ha&ton

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