Ulcerative Colitis in Female Monozygotic Twins and a Female Sibling

Vol. 61, No. 4, Part I Printed in U.S.A.

GASTROENTEROLOGY

Copyright © 1971 by The Williams & Wilkins Co.

CASE REPORTS

ULCERATIVE COLITIS IN FEMALE MONOZYGOTIC TWINS AND A FEMALE SIBLING DouGLAS R. SLEIGHT, M.D., JEFFREY E. GALPIN, M.D., AND RoBERT E. CoNDON, M.D. Department of Surgery, The Abraham Lincoln School of Medicine, University of fllinois, Chicago, Illinois

A family constellation with asynchronous onset of ulcerative colitis affecting female monozygotic twins and a nontwin female sibling is reported. Neither of two nontwin brothers nor either parent was affected. Certain genetic and environmental factors are discussed and the literature of ulcerative colitis in twins and in families is summarized. A familial tendency to develop ulcerative colitis based on a polygenic and possibly sex-linked mechanism of inheritance and which requires a further activator stimulus for expression, seems most probable in the light of evidence currently available concerning familial ulcerative colitis. We report an unusual family in which ulcerative colitis occurred in monozygotic twins and in an additional nontwin sibling. The occurrence of ulcerative colitis in both members of a monozygotic pair is rare; this is the third such report. 1• 2 In addition, our twin patients represent the first reported occurrence of ulcerative colitis in female monozygotes, and this is the first report of the occurrence of ulcerative colitis in an additional sibling of affected monozygotic twins. In the light of this unusual family, the literature concerning familial ulcerative colitis has been reviewed. Case Reports Patient E. M. S. This monozygotic twin was asymptomatic until November 1964, when, at age 20, she developed the sudden onset of diarrhea and lower abdominal cramps. She had eight to 10 loose stools a day containing mucus and, on two occasions, gross blood. The abdominal cramps were intermittent, being worse with Received January 11, 1971. Accepted May 11, 1971.

Address requests for reprints to: Dr. Douglas R. Sleight, Department of Surgery, P. 0. Box 6998, Chicago, lllinois 60690.

bowel movements. She lost 40 lb in weight during the first 6 weeks of her illness. In March 1965, she was admitted to a community hospital with bloody diarrhea and anemia. Proctoscopic examination and a barium enema both demonstrated features consistent with a diagnosis of ulcerative colitis. Her hemoglobin was 9.8 g per 100 mi. Stool examinations for ova and parasites and for bacterial pathogens were negative on three occasions. She was treated with prednisolone, initially 10 mg four times a day, but later the dose was adjusted as indicated by her symptoms; administration of steroids was continued during the next 18 months. In 1966, she again developed acute symptoms and had 13 to 15 stools each day exhibiting mucus and blood, a low grade fever, and weight loss. She was admitted to the community hospital and was treated with increased doses of prednisone, salicylazosulfapyridine, and restriction of milk and milk products in her diet. On this regimen, she showed steady symptomatic improvement. She continued to do well until June 1969, when, 3 months pregnant with her first child, she developed another acute exacerbation of ulcerative colitis. She was managed through the remainder of her pregnancy and the immediate postpartum period with increasing doses of steroids. She had an uncomplicated delivery of a normal, full term infant in December 1969. In 507

508

CASE REPORTS

March 1970, she again experienced a recurrence of frequent diarrhea and weight loss and required hospitalization. Proctoscopic examination now showed a hyperemic and friable rectal mucosa at and above 5 em from the anal verge. A barium enema demonstrated involvement of the entire colon with ulcerative colitis. She was treated with salicylazosulfapyridine and increased doses of prednisone and responded with a gradual decrease in the frequency of her bowel movements. Since then she has been maintained on salicylazosulfapyridine, has gained weight, and her bowel movements have decreased to two per day. Patient J. A. S . This nontwin sister was asymptomatic until August 1966, when, at age 21, she developed sharp, right lower quadrant pain accompanied by diarrhea, nausea, and vomiting. She was admitted to a community hospital; a diagnosis of acute appendicitis was made and a laparotomy was performed; the appendix was normal. She was then transferred to another hospital. Two days after admission to the second hospital, a diagnosis of colon perforation was made. An emergency ileostomy and total colectomy were done; the rectum was not excised. Postoperatively, an abscess developed about the ileostomy stump and was incised and drained. No other complications occurred and subsequently she was discharged to home. Three months later, J. A. S. was readmitted to the community hospital with symptoms suggestive of a subdiaphragmatic abscess. She was started on systemic antibiotics and transferred to the University of Illinois Hospital where antibiotic therapy was continued; within 2 weeks the patient's symptoms subsided. She did well for the next 8 months and then had another symptomatic exacerbation. Rectal and proctoscopic examination revealed active ulcerative colitis of the unresected rectosigmoid stump. Stool cultures for pathogens and examination for ova and parasites were negative. She was readmitted to the University of lllinois Hospital and, in July 1967, an abdominal-perineal resection of the rectum was performed. The excised tissues showed the gross and microscopic morphology typical of ulcerative colitis. The patient was last seen 2 years after rectosigmoid excision; she was asymptomatic and fully active. Patient E. M. V. This monozygotic twin was asymptomatic until August 1967, when, at age 24, she began to experience episodes of bloody diarrhea. Six months later, with her symptoms steadily increasing in severity, she was admitted to a community hospital where proctoscopic examination demonstrated an ulcerated rectum.

Vol. 61, No. 4, Part 1

Other examinations, including barium enema and studies for ova and parasites, were interpreted as normal. A diagnosis of ulcerative colitis was made and the patient was started on steroid medication and discharged. One month later, she was readmitted to the community hospital because of an exacerbation of symptoms. Steroid dosage was increased and she was transferred to the University of lllinois Hospital. Proctoscopic examination and a barium enema demonstrated severe ulcerative colitis of the entire colon. Her condition progressively improved; she was discharged and continued to take maintenance steroids. In 1968, E. M. V. became pregnant and subsequently delivered an otherwise normal infant 1 month prematurely. Immediately after delivery, her ulcerative colitis exacerbated markedly and high doses of steroids were necessary to control her symptoms. She eventually responded and was again discharged to home on chronic maintenance steroid medication. Six months later, she had a further acute relapse while still on steroid therapy and was readmitted to the University of lllinois Hospital with active rectal bleeding. Striae, moon facies, and a buffalo hump were noted on physical examination at this time. The patient was anemic and had Giardia Lamblia in her stool; no other pathogens or parasites were identified. Sigmoidoscopic examination and a rectal biopsy were consistent with ulcerative colitis. A colectomy, proctectomy, and ileostomy were performed in July, 1969. The gross specimen showed the pseudopolyposis typical of severe ulcerative colitis. Her postoperative course was complicated by wound abscesses which required drainage. Her ileostomy stoma functioned well. When last seen 14 months postoperatively she was asymptomatic and fully active.

Family Data The patients we report are members of a family of five siblings (fig. 1). The affected sisters have two older brothers,

FIG 1. Pedigree for ulcerative colitis.

October 1971

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both of whom are living and totally asymptomatic. There is no ancestral history of ulcerative colitis or of any disease exhibiting diarrhea, anemia, abdominal pain, or weight loss. The mother states that her children all were raised in similar circumstances; all were breast-fed, were weaned at approximately 6 months, and none experienced any difficulties with toilet training. There is strong evidence that these twins are truly monozygotic. They look very much alike and their mother states that even close friends "couldn't tell them apart until they were teens." Their blood was found to have identical antigens when tested with these antisera: ABO, Rh, MNS, P, I, Kell-Cellano, Duffy, Lutheran, Kidd, and Lewis. The probability, using the tables of Smith and Penrose, 3 that they are monozygotic twins is 0.983. Their fingerprints are acceptable as those of monozygotic twins according to the criteria of Hamilton et al. 4

Discussion Study of monozygotic and dizygotic twins is important in delineating hereditary and environmental factors in the etiology of disease. Monozygotic twins represent environmental and genetic consistency, while dizygotic twins represent environmental consistency but vary in genetic composition. If a hereditary etiology of a particular disease is assumed, then one would expect the second of a monozygotic TABLE

Auth or!:'

1. Reports of ulcerative colitis in twins Reference

Gregg and Baggenstoss .. Marie and Ledoux-Lebard . . . . . . . . Lyons and Postlethwait ... .. .. . . . . .. Webb Bacon . . . . . .......... .. .... Tidrick . . . . . . . . . ... Finch and Hess .... . . . . . . . . . . . . . . . . Binder et al. . . . . . . . . . . . . . . . . Binder et al. . . . . . . . . . . .. . . . . . .. Binder et al. •

•

•

•

•

0

•••

0

•

•

•

•

••

pair to be affected more frequently while the second twin of a dizygotic pair would not exhibit the disease any more frequently than in the population at large. If an environmental etiology is assumed, one would expect a similar frequency of involvement in the second twin of either monozygotic or dizygotic pairs. Including this report, there are three recorded 1• 2 monozygotic twins having both members affected with ulcerative colitis (table 1). In addition, there are 2 cases recorded in which only one member of a monozygotic pair was affected with ulcerative colitis at the time of reporting; there have been no subsequent follow-up reports of these pairs. 5 • 6 Six cases of ulcerative colitis occurring in dizygotic twins have been reported, 2 with both twins affected 7 • 8 and 4 with only one member of the pair involved. 9 • 10 Data in the literature regarding familial ulcerative colitis involving twins are biased since it is more likely that monozygotic rather than dizygotic twins with ulcerative colitis will be reported, that dizygotic twins with both members affected will be reported more frequently than when only one member is affected, and that affected twins will be reported more frequently than sibling pairs. The effect of such bias would be to increase disproportionately the recorded frequency of affected twins. Since there have been only three sets of monozygotic twins reported which were affected with ulcerative colitis, the number seems

5 6 1 2 7

s• 9 10 10 10

Type of twinning<'

M M M M D D D D D D

Number involved Comments One

Both

6 2 66

66 66 22

1 1 1 1

a M. monozygotic; D, dizygotic. • Personal communication to Drs. J . B. Kirsner and J. A. Spencer.

Concordance for liver disease Onset at 14 years old 4 years between onset 2 years between onset

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CASE REPORTS

too small for the etiology of this disease to be purely genetic. The first report of ulcerative colitis occurring in more than one member of a family was made in 1909 by Allchin. 11 The total number of reported instances of familial ulcerative colitis is now 247 (tables 1 and 2). The majority of these families have only two members affected. In 22 instances, three members are affected, and in four instances, four family members are afflicted with ulcerative colitis. Morris has reported a family in whom ulcerative colitis was present in three generations with a total of eight family members affected. 33 The incidence of familial ulcerative colitis recorded in the literature ranges between 0.6 and 16% with the average familial incidence being 250. Among families with ulcerative colitis, siblings are most frequently affected. It TABLE

might be anticipated that affected sibling pairs would follow the sex distribution of normal sibling pairs, i.e., twice as many brother-sister pairs as brother-brother, or sister-sister pairs. In fact, brother-sister pairs are found with the same frequency as brother-brother and sister-sister pairs, indicating that the mode of genetic transmission, if any, is not simple. From an environmental standpoint, it has been suggested 23 that an infectious etiology of ulcerative colitis might be assumed from the more frequent occurrence of the disease in the mother of affected families, since she is the usual family food handler. The literature which we have reviewed shows a mother-sibling occurrence of ulcerative colitis in 34 cases compared with father-sibling occurrence in only 14 cases. In our patients, neither parent was affected.

2. Reports of familial ulcerative colitis No. of

No. of familes with

Author

... . . .. All chin Bargen . . . . . .. .. Spriggs . ... Moltke Hommes and Leenmans . Feder Brown and Scheifley Jackman and Bargen . . . . Sloan eta!. Paulley ... Paulson Kirsner and Palmer . Felsen and Wolarsky .. . Bacon Schlesinger and Platt Houghton and Naish . Paris and Heraud . ... . . Finch and Hess Comes and Stecher Barker Wigley and MacLaurin . Lennard-Jones eta!. Kirsner and Spencer . Maratka and Sera . Binder eta!. .. . Hammer eta!. ... . .

Total .

. .

...

.. . . .. . . . .

ence

11 12 13 14 15 16 17 18 19 20 21 22 23 7 24 25 26 9 27 28 29 30 8 31 10 32

families in rep?rted expenence

One

Two

member

members

affected

affected

with more

Incidence of familial

families

No. of Refer·

Three members affected

Four

than single

ulcerative

members

member

colitis

0 0 0 0 0 0 0 0 0 0 0 0

affected

affected

88 688 46 112

87 683 45 107

1 5 0 5

87 2485 891 1971 147

86 2470 833 1945 125

120 1188 437

114 1169 434

1 15 7 23 22 6 6

0 0 1 0 0 0 0 1 3 0 0 0

3

0

0

169 74 17 200 50 200 90 1009 594 144 98

163 71 15 191 42 195 85 950 584 576 91

4 3 2

2 0 0

0 0 0

7 4 3 41 6 8 7

1 1 2 11 0 0 0

0 0 0 4 0 0 0

6 3 2 9 8 5 5 59 6 8 7

180

22

4

230

1

10,905

1 5 1 5

1.1 0.7 2.2 4.5

1 15 8 26 22

1.5 0.6 0.9 1.3 15.0

6 19 3

5.0 1.6 0.9 17 .0 3.5 4.1 11.7 4.5 16.0 2.5 5.5 5.5 1.0 5.5 7.0 2.1

October 1971

CASE REPORTS

Other information concerning a possible environmental etiology of familial ulcerative colitis can be gained from the time sequence of onset of ulcerative colitis. In the family we report, twin E. M. S. was the only sibling still living at home and was the first person affected. The other twin, E. M. V., had left home a year earlier and she did not exhibit symptoms of ulcerative colitis until 4 years later. The nontwin sister, J. A. S., left home before the onset of symptoms in E. M. S. and had the onset of her disease nearly 2 years later. The two unaffected brothers had left home 2 and 4 years before the initial appearance of symptoms of ulcerative colitis in E. M. S. The time sequence of onset of ulcerative colitis in this family permits at least two alternate interpretations. The affected members could all have contracted their ulcerative colitis at home. If so, then one would have to postulate different inoculation or incubation times, since the onset of colitis in individual family members occurred over a 3-year span and, in one member, occurred 4 years after leaving home. In the family reported by Morris 33 of three generations with eight family members affected, in only one case were two members living in the same household at the onset of their ulcerative colitis. An alternative interpretation is that this family exhibits a sex-influenced predisposition to ulcerative colitis. The involvement of three females without the involvement of male siblings, although perhaps due to chance alone, lends support to an etiological hypothesis involving a sexinfluenced mechanism. The age of appearance of ulcerative colitis in our patients fits the early onset pattern noted by Evans and Acheson 34 and the female preponderance seen among series of early onset colitis reviewed by Burch et al., 35 suggesting predisposition to early onset ulcerative colitis which is polygenic in nature. One or more autosomal predisposing factors, in addition to genetic factors, must be implicated to account for the random initiation of disease. In conclusion, the relatively small number of monozygotic twins reported with ulcerative colitis is evidence against a

511

purely genetic basis for the disease, for one would expect a greater number of reports of affected monozygotic twins. The time-onset pattern in this family may be interpreted as support for an environmental or a genetic etiology. The age of onset and sex of the affected siblings fit most closely a polygenic familial predisposition, possibly sex-linked, which requires a further genetic or environmental stimulus for expression. REFERENCES 1. Lyons CK, Postlethwait RW: Chronic ulcerative colitis in twins. Gastroenterology 10:545-550, 1948 2. Webb LR: The occurrence of chronic ulcerative colitis in twin males. Gastroenterology 15:523524, 1950 3. Smith SM, Penrose LS : Monozygotic and dizygotic twin diagnosis. Ann Hum Genet 19: 273-289, 1955 4. Hamilton WJ, Boyd JD, Mossman HW: Human Embryology, Prenatal Development of Form and Function. Third edition. Baltimore, Williams & Wilkins Co, 1964, p 155 5. Gregg JA, Baggenstoss AH: Discordance for ulcerative colitis in identical twins concordant for cholestatic liver disease. Amer J Dig Dis 15: 667- 671, 1970 6. Marie J, Ledoux-Lebard G : Rectocolite hemorrhagique chex un enfant. Caractere familial de !'affection. Arch Mal Appar Dig 31:76- 86, 1942 7. Bacon HE: Ulcerative Colitis. Philadelphia, JB Lippincott Co, 1958, p 2-3 8. Kirsner JB, Spencer JA: Family occurrences of ulcerative colitis, regional enteritis, and ileocolitis. Ann Intern Med 59:133-144, 1963 9. Finch SM, Hess JH: Ulcerative colitis in children. Amer J Psycho! 9:819-826, 1962 10. Binder V, Weeke E, Olsen JH, et al: A genetic study of ulcerative colitis. Scand J ~astroent 1: 49- 56, 1966 11. Allchin WH: Ulcerative colitis. Proc Roy Soc Med 2:59-63, 1909 12. Bargen JA: Complications and sequelae of chronic ulcerative colitis. Ann Intern Med 3:335352, 1929 13. Spriggs El : Chronic ulceration of the colon. Quart J Med 27:549-555, 1934 14. Moltke 0 : Familial occurrence of non-specific suppurative coloproctitis. Acta Med Scand (supp 77) 78:426-432, 1936 15. Hommes M, Leenmans AM: Familial colitis gravis. Nederl T Geneesk 80:5131-5137, 1936 16. Feder lA : Chronic ulcerative colitis: an analysis of 88 cases. Amer J Dig Dis 5:239-251, 1938

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CASE REPORTS

17. Brown PW, Scheifley CH: Chronic regional en-

18.

19.

20.

21.

22. 23.

24.

25.

26.

teritis occurring in three siblings. Amer J Dig Dis 6:257-261, 1939 Jackman RJ, Bargen JA: Familial occurrence of chronic ulcerative colitis (thrombo-ulcerative colitis): report of cases. Amer J Dig Dis 9:147149, 1942 Sloan WP, Bargen JA, Gage RP: Life histories of patients with chronic ulcerative colitis: a review of 2000 cases. Gastroenterology 16:25-38, 1950 Paulley JW: Ulcerative colitis. Gastroenterology 16:566-567, 1950 Paulson M: Nonspecific or indeterminate colitis, Diseases of the Digestive system. Third Edition. Philadelphia, Lea and Febiger, 1954, p 783 Kirsner JB, Palmer WL: Ulcerative colitis. JAMA 155:341-350, 1954 Felsen, J, Wolarsky W: Familial incidence of ulcerative colitis and ileitis. Gastroenterology 28: 412-416, 1955 Schlesinger B, Platt J: Ulcerative colitis in childhood and a followup study. Proc Roy Soc Med 51:733-735, 1958 Houghton EAW, Naish JM: Familial ulcerative colitis and ileitis. Gastroenterology 89:65-74, 1958 Paris PMJ, Heraud M : A propos des rectocolites

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hemorragiques familiales. Arch Mal Appar Dig 50:370-374, 1961 27. Cornes JS, Stecher M : Primary Crohn's disease of the colon and rectum. Gut 2:189-201, 1961 28. Barker WF: Family history of patients with ulcerative colitis. Amer J Surg 103:25-26, 1962 29. Wigley RD, MacLaurin BP: A study of ulcerative

30.

31.

32.

33. 34.

35.

colitis in New Zealand, showing a low incidence in Maoris. Brit Med J 2:228-233, 1962 Lennard-Jones JE, Cooper GW, Newell AC, et a!: Observations on idiopathic proctitis. Gut 3: 201- 206, 1962 Maratka Z, Sera J: Familial occurrence of ulcerative colitis. Gastroenterologia (Basel) 103:321325, 1965 Hammer BP, Ashurst P, Naish J : Diseases associated with ulcerative colitis and Crohn's disease. Gut 9:17- 21, 1968 Morris PJ: Familial ulcerative colitis. Gut 6:176178, 1965 Evans JG, Acheson ED: An epidemiological study of ulcerative colitis and regional enteritis in the Oxford area. Gut 6:311-324, 1965 Burch PRJ, de Dombal FT, Watkinson G: Aetiology of ulcerative colitis. II. A new hypothesis. Gut 10:277-284, 1969