CASE REPORTSCONGENITAL FIBROCYSTIC DISEASE OF THE PANCREAS_-

A REPORT OF TWO PROVED CASES OF DISSIMILAR CLINICAL TYPES IN SBLINRSBY

AGNES R. MACGREGOR, M.D., F.R.C.P.EdL, and KENNETH RHANEY, M.B., Ch.B.(From the Department of Child Life and Health, Edinburgh University)

In her important paper on cystic fibrosis of thepancreas, Andersen (1938) showed that this diseasemanifests itself as one of three clinial syndromes.This has been confirmed by many subsequentworkers. The syndromes have the following salientfeatures:

(1) Newly born infants who die within a week ofbirth from intestinal obstruction due to inspissationof meconium, sometimes associated with peritonealbands, volvulus or atresia.

(2) Infants between one week and six months old,in whom the principal features are early failure tothrive, often despite a good appetite, large fattystools, and intolrance to fat in the diet. Theseinfants invariably present an intrctable infectionof the respiratory tract resembling whooping-cough,with paroxysms of coughing and cyinosis. Thisinfection appears to be the immediate cause ofdeath.

(3) Children over six months of age, who presentthe clinical features of the coeliac syndrome.

it is now recognized that congenital fibrocysticdisease of the pancreas has a high familial incidence.In a recent paper on the genetics of the disease,Andersen and Hodges (1946) reviewed the literatureand concluded that 'it occurs among siblings, twinsand more distant relatives with a distribution whichis compatible with the hypothesis that it is carriedas a relatively infrequent hereditary trait.' Theycollected from the literature several instances inwhich one sibling suffered from congenital intestinalobstruction and another from proved pancreaticdisease presenting one ofthe other cinical syndromes(Flax et al., 1942; Deem and McGeorge, 1941;Attwood and Sargent, 1942; Philipsborn et al.,1944). In none of these instances were bothsiblings examined at autopsy. The following caserecords illustrate the occurrence of dissimilarclinical types in siblings, one of whom suffered fromcongenital intestinal obsuction. Both were provedby post-mortem examination to have cystic fibrosisof the pancreas.

Case ReportsCase 1. The patient was a female infant aged

four months at the time of admission to hospital.She was the second child ofher parents, the first-bornbeing a healthy girl of six years. She was admittedbecause of cough since birth, and stridor for twomonths. She was said to have been one monthpremature (birth weight 5j to 6 lb., spontaneousdelivery). She was well at birth, but attempts toinstitute breast feeding failed after three days. Shewas given boiled cows' milk, and later NationalDried Milk, in appropriate amounts with theaddition of adequate vitamins. The appetite wasgood until one week before admission, when itbecame capricious, and at some feeds only oneounce Was taken.She was said to have had a cough since birth, but

this did not cause distress. Two months beforeadmission she began to vomit after feeds, anddeveloped stridor, which was accompanied bycyanosis during the last month. At that time shedeveloped acute catarrh with nasal discharge. Thecough became worse, with paroxysms. This wasassociated with great distress and cyanosis, andaphonia developed. During the last week beforeadmission, the symptoms became more severe.Diarrhoea developed, ' fiequent loose, brown stools 'being passed. The appetite became poor and shebegan to lose weight.

CUNICAAL ExAMNATioN. The infant was wellproportioned but of poor nutrition, her length being22 inches, and her weight 8 lb. 131 oz. The abdomenwas not distended, and no enlargement of the liveror spleen could be detected. Muscle tone was poor,and great weakness resulted from the paroxysms ofcougbinSg There was slight cyanosis. The alaenasi were moving. There was no nasal discharge.The fauces were slightly congested. The chest washeld in the position of inspiration. The lower ribswere indrawn on inspiration. A resonant percus-sion note was obtained, and on auscultation theexpiratory phase was prolonged.No abnormality of the alimentary system was

found. The nervous system was normal. Thewhite blood count was 12,000 per c.mm ofblood, haemoglobin 75 per cent. (Sahli). The

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FIBROCYSTIC DISEASE OF PANCREAStemperature was 980 F., the pulse 134 per minute,and respiration 36 per minute. X-ray examinationon admission revealed 'no gross pulmonarylesion.' Three days before death a second examma-tion showed 'exaggerated shadows at both bases,consistent with bronchiectasis.'FURTHER PROGRE. Death occurred after six-

teen days in hospital. During this time she becameprogressively weaker and the respiratory difficltymore severe. Vomiting followed all feeds, and thestools became frequent, offensive, and watery.They were not noticeably fatty. During the wholeperiod in hospital the temperature was normal orsubnormal, except for two occasions when it roseto 990 F. Owing to the cyanosis, oxygen wasadministered continuously. Laryngoscopic examina-tion revealed no obstruction in the larynx, which wasinflamed. There was thick secretion in the pharynx.Six days before death she collapsed and was pale,cold, cyanosed, and gasping for breath. Penicillinwas given by intramuscular injection until death,without obvious beneficial result.PosT-MoRTm REPORT. The body was that of a

small, emaciated female infant. The chest was heldin the position of inspiration, with the ribs elevated.There was no jaundice of the skin. The larynx,trachea, and main bronchi were filled with thickyellow pus, and the mucous membrane was slightlycongested. There was no anatomical abnormalityof the larynx.The left pleural sac contained air under pressure,

but the left lung was only partly collapsed. Inboth lobes there was interstitial emphysema, withlarge air bullae under the pleura and in the septa.The right pleural sac was healthy, and the rightlung showed only vesicular emphysema. No con-solidation could be detected in either lung.Throughout the whole bronchial system there wassevere purulent bronchitis, all the bronchi down tothe smallest visible twigs being filled with thickyellow pus. There was no obvious dilatation ofthe bronchi, and suppurative disorganization wasnot evident to the naked eye. The lymph nodes inthe roots of the lungs were a little swollen anddeep red.The heart and pericardium were healthy. The

alimentary tract showed nothing of note. Theperitoneal sac was healthy. The liver was notenlarged but was bright yellowish brown, andshowed a considerable amount of bile staining.The gall-bladder contained dark green bile, whichwas easily expressed into the duodenum. Thespleen was of appropriate size and showed nothingof interest. The kidneys were rather paler thanusual, but otherwise normal. Tne pancreas wasrather below the expected size, of about normalconsistence, but slightly nodular on the surface.It was not obviously fibrosed.The head was not examined.BACTEIuLoGIcAL REPORT. The pus in the

bronchi contained immense numbers of Gram-positive and Gram-negative bacilli, which, on

culture, proved to be a diphtheroid bacillus andBacillus latis aerogenes. Staphylococcus aureuswas not found in the direct film or on culture.

MICROscoPICAL REPORT. Pancreas (fig. 1, p. 59).The gland acini were formed of small, atrophiedcells, and their slightly dilated lumina containedplugs of inspissated secretion. Similar material waspresent in the lumina of intralobular and inter-lobular ducts, which were slightly dilated. One ofthe larger ducts in the head of the pancreas was alsodilated and its lumen obstructed by inspissatedmaterial. The islets of Langerhans were normal.In many parts there was a considerable increase ofinterlobular and interacinar fibrous tissue. Theamount varied, and in those places where it wasgreatest there was a reduction in the number ofacini.

Lung. The bronchi of all sizes were filled withmucus, among which were masses of bacteria andvariable numbers of polymorph leucocytes andepithelial cells. The inflammatory cells weresurprisingly scanty and much degenerated. Somebronchi showed a moderate amount of inflammatorycell infiltration of the wall, with both mononuclearcells and polymorph leucocytes. The epitheliallining was intact in the majority, but in some of thelarger bronchi the ciliated epithelium had beenreplaced in parts of the wall by stratified squamousepithelium. Most of the mucous glands in thewalls of the large bronchi were actively secreting,but others were lined with low cubical cells, and thelumina were dilated and contained inspissatedsecretion of a hyaline character, staining stronglywith eosin (fig. 2, p. 59). There was no bronchi-ectasis and no disorganization of the bronchialwalls. The inflammatory process had not extendedto the alveoli. There was a moderate degree ofvesicular emphysema.

Liver. There was severe fatty change, affectingprincipally the portal zones of the lobules. Therewas no increase in fibrous tissue and no abnormalityof the bile ducts was noted.SummARY. This was a case of purulent bronchitis

with cystic fibrosis of the pancreas and fatty changein the liver.

Case 2. The patient was a male infant bornsixteen and a half months after the birth of hissister (case 1). His birth weight was 5 lb. 14 oz.Delivery was spontaneous, but the baby was limpand cyanosed at birth. During the first two days-respirations were shallow and murmury, and hehad several attacks of respiratory failure withcyanosis. Chest expansion was poor, and a fewcrepitations were heard. Meconium was said tohave been passed on two occasions: once on thesecond day and once on the third day. Noabnormality of the meconium was noted. Deathtook place on the third day.P0r-MORTEM REPORT. The body was that of a

male infant weighing 5 lb. 14 oz. The umblLicalcord was partly dried. There was slight jaundice.

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ARCHIVES OF DISEASE IN CHILDHOODWhen the abdomen was opened a greatly dis-

tended loop of bowel presented. It was approiu-mately six inch long, and its lower end was fourinches proximal to the ileo-caecal valve. It con-tained meconium, which was of normal colour butmore viscid and cohesive than usual. Proximal tothis loop no abnormality was noted in the boweland its contents. At the distal end of the loop thecharacter of the contents underwent a suddenchange, and the remaider of the ileum contained asmall quantity of pale green, thick, paste-likematerial, which could be forced along the bowelonly with great difficulty. The ileo-caecal valvewas patent. The caecum contained a little of thesame material. The colon contained white mucusand was contracted. Obstruction was apparentlypresent at the distal end of the dilated loop, but hadproduced no hypertrophy of the wall. There wasno sticture, peritoneal band, atresia, or volvulus.The pancreas was macroscopically normal. The

liver was intensely congested. The biliary passagewere healthy. Both kidneys contained heavydeposits of uric acid crystals.The larynx, trachea and main bronchi contained

a small quantity of frothy, blood-stained fluid. Thepleural and pericardial sacs were healthy.Both lungs showed widespread pneumonia, only

a small strip at the anterior border of the rightlower lobe being healthy. The remainder of bothlungs was intensely congested and of greatlyincreased bulk and consistnce. The right lungwas more affected than the left. The cut surfaceswere very moist, and turbid fluid was expressed-from the bronchi.

The heart showed no-developmental abnormality.Both atria were distended. The ventricles werecontracted. The oesophagus was congested through-out its length. The thymus gland was healthy.The venous sinuses of the dura mater, and the

vems in the lepto-meninges, were congested. Thebrain substance was healthy.

BAcrri oLOGIcAL REPORT. A culture from thelung yielded a growth of Bacillus coli and Staphy-lococcus albus.MICROscoPICAL REPORT. Pancreas (fig. 3, p. 59).

Atrophy of the acinar tissue was revealed. In mostof the lobules the acini were reduced in number andin size, being composed of small cubical or flattenedcells. In many acni the lumen was slightly largerthan normal and was filled with inspissated secretionof hyaline appearance. Some of the acinar cellscontained apparently normal secretory granules,but in others there were large, faintly acidophil,hyalie bodies, which occupied much of the cyto-plasm, and appeared to be of the same nature as theinspissated material in the lumen (fig. 4, p. 59). Incontrast, some acin, lined by atrophied cells,showed no visible lumen. The small interlobular,and many intralobular, ducts were slightly dilatedand filled with inspissated secretion. Some of theintrlobular ducts were empty and not dilated.The lager pancreatic ducts were not present in the

tissue available for eamination. The islets ofLangerhans were greatly reduced in number andsize. There was a slight increase in interlobularand interacinar stroma, which was oedematous butshowed no evidence of inflammation.

Lung. The lungs contained a large quantity ofvernix, some of it in lumps, but most of it formingthick membranes lining the walls of terminalbronchioles and alveolar ducts. Proximal to it therespiratory ages were over-distended, but thedistal parts were atelectatic and compressed.Widespread patchy exudate had developed inrelation to the vernix and was composed maily ofpolymorph leucocytes. Other areas were filled withblood and oedema fluid. There was no abnormalityof the bronchial mucois glands.The liver showed intense congestion, and in the

portal zones some of the cells contained smallglobules of fat.

Oesophagus. There were no pathological featuresapart from intense congestion of the submucous coat.The spleen showed nothing of interest.Kidneys. The collecting tubules were dilated and

contained the stnruturekss debris found in associa-tion with deposits of uric acid crystals.SuMMARY. This was a case of meconium ileus

associated with cystic fibrosis of the pancreas.There was inhalation of the vernix, with pneumonia.

C_seThe occurrence of pancreatic lesions character-

istic of congenital fibrocystic disease in these twosiblings provides strong evidence in favour of theconclusion of Andersen and Hodges (1946) thatmeconium ileus in the newborn has the sameetiology as the two clinical syndromes that revealthemselves in later infancy. It also confirms theconception that the clinical type of the disease isdetermined by the age at which the pathologicalprocess in the pancreas results in a severe deficiecyof exocrine secretion. If this stage is reached atthe time of birth, meconium ileus results; if in theearly months of life, the respiratory type; if in laterinfancy, the coeliac type,

If the pathological changes are due, as is believed,to inspissation of secretion in the acini and ducts,and ifthe obstruction thus caused persists, the degreeof atrophy, dilatation and fibrosis will depend, atleast in part, upon the duration of life. Accordinglyall these features were more fully developed in thepancreas of the older child, although at the time ofher birth the pancreatic function was less impairedthan in the case of the infant who developedmeconium ileus.

Stenosis or atresia of the main pancreatic duct hasbeen found in a proportion of cases of congenitalfibrocystic disease (Kornblith and Otani, 1929;Hurwitt and Amheim, 1942; Kauffmann andChamberlaini, 1943). Unfortunately the mainpancreatic duct was not examined in either of thecases under discussion. In case 2 certain featureswere found that could not readily be explained by

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FIBROCYSTIC DISEASE OF PANCREAS

Fwa. 2-Case 1. The wall of the bronchus showsFiG. I.-Case 1. Pancreas shows dilated acini and dilatation of mucous glands, with ispissation of secre-ductscontaining inspissated secretion. Other acn are tion. H. and E. x 160.atrophied. Inter- and intra-loular stroma is increased.H. and E. x 115.

FIG. 4.-Case 2. Pancreas. Acinus showing hvalinebodies in the cells and inspissated secretion in the lumen.H. and E. X 650.

FIG. 3.-Case 2. The pancreas shows atrophy ofacini. The ducts and some acini are dilated and containinspissated secretion. The stroma is increased. H. andE. x 160.

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60 ARCHIVES OF DISEASE IN CHILDHOODobstruction in the main duct, and suggested anabnormality of the acinar cells. Some of theintralobular ducts that showed no evidence ofobstruction, being undilated and empty, wererelated to acini that contained inspissated secretionand were slightly dilated. Some acinar cellscontained hyaline bodies similar to inspissatedsecretion in the lumen. This strongly suggests thatthey were producing an abnormal secretion.

In case 1, changes suggesting an abnormality ofsecretion were found in the mucous glands of thebronchi. Farber (1944b) has emphasized that thepancreas is not the only gland in which changes inthe physical character of the secretion occur. Tothe involvement of the tracheal and bronchialmucous glands he attributes the accumulation ofthick mucus in the respiratory passages, which causesthe paroxysmal cough and respiratory obstruction.

It thus appears that the characteristic pathologicalchanges of this disease are the result of an error ofsecretory function, and that other glands in additionto the pancreas may be affected. The names bywhich the condition has become commonly known,fibrocystic disease, or cystic fibrosis of the pancras,are, therefore, unfortunate, for as May (1947) hasobserved, 'The pathology includes much more thanfibrosis, but the name " cystic fibrosis " which hasbeen proposed is definitely misleading. Thedilated ducts and acini are not true cysts, and thereactually is another rare condition in which thereis an involvement of the pancreas with numeroustrue cysts.'

In most of the reported cases the organismresponsible for the respiratory infection wasStaphylococcus aureus. The character of thepurulent bronchitis in case 1 was similar to thatfound in other cases of fibrocystic disease of thepancreas in which Staphylococcus aureus was thecausative organism. This organism was not presentin films and cultures made at autopsy: these yieldeddiphtheroid bacilli and Bacillus lactic aerogenes.The character of the pus and the microscopicalappearance of the bronchi were in keeping with aninfection of low virulence. It is possible thatStaphylacoccus aureus had been present, and hadbeen eliminated by penicillin therapy, but no

bacteriological investigations of the bronchialsecretions were made during life.

SummaryThe occurrence of fibrocystic disease of the

pancreas in siblings is reported. One died ofrespiratory infection at the age of four months, andthe other with meconium ileus at the age of twodays. In both cases the diagnosis was proved byautopsy.The pathological changes in the pancreas appeared

to result from an abnormal secretion of the acinarcells. A similar abnormality was present in thebronchial mucous glands of the infant that died ofrespiratory infection.

We wish to express our thanks to Prof. CharlesMcNeil, and Dr. W. F. T. Haultain for permissionto publish the cases and for the use of the clinicalrecords. We are also indebted to Dr. J. L. Hender-son for clinical particulars of both cases and forhelpful criticism. We are grateful to Prof. R. W. BEllis for his help and encouragement.

REFERENCESAndersen, D. H. (1938). Amer. J. Dis. Child., 56, 344-

and Hodges, R. G. (1946). Ibid., 72, 62.Attwood, C. J. and Sargent, W. H. (1942). Radiology,

39, 417.Deem, H. and McGeorge, M. (1941). Aew Zealand

med. J., 40, 155.Farber, S. (1944a). J. Pediat., 24, 387.

(1944b). Arch. Path., 37, 238.Flax, L. J., Barnes, M. and Reichert, J. L. (1942)_

J. Pediat., 21, 475.Hurwitt, E. S. and Arnheim, E. E. (1942). Amer. J.

Dis. Child., 64, 443.Kauffmann, W. and Chamberlin, D. B. (1943). Ibid.,

66, 55.Kornblith, B. A. and Otani, S. (1929). Amer. J. Path.,

5, 249.Mav, C. D. (1947). Chronic Disturbances of Nutrition

in Diseases of Children, ed. Paterson, D. andMoncrieff, A., 1, 337. London.

Philipsborn, H. F. Jr., Lawrence, G. and Lewis, K. C-(1944). 1. Pediat., 25, 284.

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