GASTROENTEROLOGY

1991;100:1638-1643

Frequency of Inflammatory Bowel Disease in Offspring of Couples Both Presenting With Inflammatory Bowel Disease RACHEL A. BENNETT, PETER H. RUBIN, and Division of Gastroenterology, New York, New York

Department

of Medicine,

A private practice was surveyed for prevalence of inflammatory bowel disease (IBD) in husband-wife partners and in their children. Among approximately 2500 patients with IBD in our files, 19 couples were identified. They were subdivided into group A (n = 5) in which both partners had symptoms of IBD before marriage; group B (n = 7) in which only one spouse had IBD before marriage and the other partner experienced symptoms afterwards: and group C (n = 7) in which neither spouse had symptoms before marriage but IBD subsequently developed in both. In group B, the disease developed in the second spouse 2-16 years after marriage (mean, 6.4 years). In group C, IBD developed in the first spouse 0.3-41 years after marriage and in the second spouse 1-14 years after the first spouse (mean, 6.8 years). Thirty-five children have been born to 16 of the couples. Two children died before age 20. Of the surviving 33 children, IBD has already developed in 12 (36%). Among the other 21 unaffected children, 1 had uveitis at age 9 and 10 are still under the age of 21, perhaps too young to have yet developed IBD. The frequency of IBD in children was slightly higher if both parents had already developed IBD at the time of conception (67%) compared with when only 1 parent (50%) or neither parent (50%) had developed IBD aNhen conception occurred. Although these data do not distinguish genetic from environmental factors, they show a higher risk of IBD in children when both parents have this illness.

T

he pathogenesis of inflammatory bowel disease (IBD) has been ascribed to genetic influences, environmental factors, or a combination of the two. Evidence for a genetic basis of transmission includes frequent occurrence of IBD among first degree relatives and other family members (l-11), increased prevalence in certain ethnic groups (12-15), higher

The Mount

DANIEL Sinai

H. PRESENT

School

of Medicine,

rates of concordance for IBD among monozygotic than occurrence of IBD in among dizygotic twins (16-23), family members living apart for long periods of time, nonepidemic character of IBD, and paucity of reports of IBD among nonconsanguineous family members (1). Not consistent with a genetic model has been the failure to demonstrate an association between IBD and any particular HLA or blood group antigen, an inheritable protein, enzymatic, or metabolic defect, or a unique chromosomal abnormality (1,2). Environmental factors that have been scrutinized include smoking (24-27), oral contraceptive use (28agents such as atypical mycobacteria 32), infectious (33~37), lack of breast-feeding, and early weaning (38-40). The increased incidence of IBD in recent decades further supports an environmental factor, because the increase occurred over too short a time span to be accounted for by genetic transmission (15,22). However, no agent has been convincingly isolated, and Koch’s postulates have not been satisfied for any infectious agent. Finally, some investigators believe that IBD is a disease with both a genetic and environmental basis, with heredity determining an individual’s response to environmental factors (2). There are only rare reports of IBD in individuals who have had a prolonged close contact with a diseased patient or IBD after a presumed exposure to a common source of infection (41). Only 15 documented cases of IBD have been reported developing after marriage, either in both members of a husbandwife couple or in the previously healthy spouse of a patient with IBD (5,42-51). To further explore the roles of genetics and environment in the pathogenesis of IBD, we now report an additional 19 pairs of

used in this paper: CD, Crohn’s disease. 8 1991 by the American Gastroenterological Association 0016-5085/91/$3.00

Abbreviation

June

1991

IBD IN OFFSPRING

husband-wife couples with IBD and the prevalence their 35 children.

in

OF COUPLES

Table 1. Timing of Onset of Inflammatory Relative to Date of Marriage

WITH IBD

1639

Bowel Disease

1 before,

Materials

and Methods

In a survey

of our private practice of approximately we have identified 19 married couples with IBD. The cases were identified at the time of the patients’ initial office evaluation. The new patients were specifically asked if they had any relatives with IBD. All patients’ family data (as well as other IBD characteristics, such as extraintestinal manifestations) were and are currently recorded on a standard form. This form has been used since the inception of the practice and up to the duration of this study (from 1966 to 1988). If it is determined in subsequent visits that another member of the family or a spouse has developed IBD, this is recorded on the “initial” data sheet. These standard forms of all patients were reviewed to identify the cases reported in this study. The patients come primarily from the greater metropolitan New York area and New Jersey. Approximately 80% are married either the and 70% are Jewish. For each couple studied, husband, wife, both, or one or more of the children were interviewed via telephone. The following facts were ascertained: dates of birth, marriage, onset of symptoms, and diagnosis of IBD; other diseases; consaiiguinity; location of residence; religion, smoking history: dates of birth of all children, onset of symptoms, and diagnosis of IBD in affected children; and type of IBD in parents and children. We reviewed the charts and radiological and/or biopsy reports confirming the diagnosis of IBD in the 26 subjects 12 subjects who are our patients. For all the remaining (spouses of our patients), we obtained the radiological and/or pathology reports and reviewed them fo; accuracy of diagnosis of IBD. Couples were assigned to one of three groups (A, B, or C) based on the timing of onset of symptoms of disease in each partner relative to the date of marriage. If the onset of symptoms of IBD occurred before marriage in both the husband and wife, the couple was placed in category A; if either the husband or wife (but not both) had symptoms of IBD before marriage and the spouse developed symptoms after marriage, the couple was assigned to group B; and if both husband and wife were symptom free before marriage but developed symptoms after marriage, they were included in group C. 2500

Both before marriage

IBD patients,

Results None of the couples studied were consanguineous. Of the 38 subjects, 33 (87%) are Jewish, 4 (10.5%) Catholic, and 1 (2.5%) Protestant. The index case was one of the parents in 18 of the spouse pairs and a child in one of the spouse pairs (C5). His first visit into the office was at age 25, and at that time we identified that both parents had IBD. Five couples were assigned to group A, 7 to group B, and 7 to group C (Table 1). In group A, the mean age of disease onset was 18.3 years. Three couples (A2, A4,

Group No. of couples

A 5

1 after marriage B 7

Both after marriage C 7

and A5) were concordant for Crohn’s disease (CD) and 1 (A3) for ulcerative colitis (UC), and 1 (Al) was discordant. In group B couples, the mean age of disease onset was 22.6 years in the first spouse and 34.2 years in the second spouse. Two couples (B3 and B4) were concordant for CD and 1 (B5) for UC, and 4 were discordant. The partner affected at the time of marriage was the husband in 3 couples, and the wife in 4. The first spouse to develop IBD had CD in 4 of 7 pairs; the second spouse developed CD in 4 of 7 pairs. The disease appeared in the second spouse an average of 6.4 years after marriage. The discordant couples were equally divided as to whether CD or UC came first. In group C, the mean age of disease onset was 33.7 years in the first spouse and 40.4 years in the second spouse. One couple (Cl) was concordant for CD, and the other 6 couples were discordant. The first spouse to develop IBD was the husband in 2 couples (C4 and C5) and the wife in the remaining 5 couples. The first spouse to develop IBD had CD in 2 of 7 pairs, whereas the second spouse developed CD in 6 of 7 pairs. The first spouse developed IBD an average of 11.9 years after marriage and the second spouse an average cf 6.8 years after the first. In 5 of the 6 discordant couples, UC came first. In 2 couples (C2 and C4), the spouses developed IBD within 2 years of each other (Table 2). A review of the family history of the 19 husbands and wives with IBD shows that 8 of the 38 (21%) spouses had a history of a first degree relative with IBD (3 in group A, 1 in group B, and 4 in group C). One spouse in group C had a second degree relative with IBD, and another spouse in group A had a more distant relative with IBD. Twenty-eight of the spouses had no known relatives with IBD. Thirty-five children were born to 16 couples (3 couples are childless). Two children died before age 20 (1 from asthma and 1 from leukemia); of the remaining 33, 12 (36%) have already developed IBD at a mean age of 23.3 years. None of the remaining 10 children who are younger than 20 years has developed IBD, but 1 developed uveitis at the age of 9 years. One child from parents C2 died at age 29 of surgical complications of his UC (Table 3). Group A parents had the highest frequency of children developing IBD, 4 of 8 (50%), with 2 of the unaffected 4 children still younger than age 20. Three

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GASTROENTEROLOGY

BENNETT ET AL.

Table 2. SDouses With Inflammatorv Bowel Disease

Couple Al A2 A3 A4 A5 Bl B2 B3 B4 B5 B6 B7 Cl c2 c3 c4 c5 C6 c7

Spouse

Yr of birth

Onset

H W H W H W H W H W H W H W H W H W H W H W H W H W H W H W H W H W H W H W

1954

1970

1949

1968 1935 1937 1940 1940 1979 1969 1964 1966 1940 1970 1980 1971 1964 1952 1953 1942 1970 1963 1951 1976 1965 1971 1981 1967 1960 1958 1975 1967 1979 1980 1951 1959 1967 1963 1982 1972

1919 1921 1924 1924 1953 1955 1942 1944 1932 1934 1949 1951 1926 1928 1924 1924 1943 1947 1919 1922 1945 1946 1945 1946 1902 1901 1913 1914 1954 1957 1921 1924 1940 1943 1940 1942

Type of IBD CD UC CD CD UC UC CD CD CD CD UC CD CD UC CD CD CD CD UC UC CD UC CD UC CD CD CD UC CD UC CD UC UC CD CD UC CD UC

Yr after marriage till onset

Table 3. Children Born to Parents with Inflammatory Bowel Disease Couple Al A2 A3

A4 A5

7 5 5

Bl B2 B3 B4

7 B5 3 B6 B7 16 Cl 2 14 0.3 30 28 41 33 3 4

c2

c3 c4 c5

a

16 5 1 21 10

Vol. 100, No. 6

C6 c7

Age (YN sex

41/F 34/F 32/M 30/M 28/M 27/F

Age at onset

Type of 1BD

21 31 7

CD UC CD

21

CD

16

23

CD CD

32

CD

14/M 12/M 23/M 8/F 26/M 23/M 40/F 32/M 28lM 9/M 7/M -

Uveitis

9

15/M 12/M 17/M 13/M 55/F -lM 51/F 44/F 39/F 7/F 41/M 35/M 32/M -IM 23/F 20/F 20/F -IF

34 19 35

CD UC (29)” CD

21 20 (20)”

CD UC

(14)”

“Age at death.

of the 11 children (27%) born to group B couples have developed IBD, with 5 of the remaining 8 still younger than age 20. One of these 5 has chronic uveitis. Of the 16 children who were born to group C couples, 5 (31%) have already developed IBD. Of the remaining 11 children in group C, 2 died of non-IBD causes before the age of 20 and 3 are still younger than 20 years of age. Combining all three groups of offspring, 12 of the 23 children (52%) who have reached age 20 have already developed IBD (Table 3). These 12 affected children are the offspring of 6 couples. With respect to types of IBD the children developed in relation to the type of IBD in parents, CD predominates in the offspring regardless of what type of IBD the parents manifested. If both parents had CD, all of the affected children developed CD (Table 4). The children were divided into three groups accord-

ing to whether both parents, 1 parent, or neither parent had yet developed symptoms of IBD at the time of the children’s conception. Fifteen children were conceived at the time when both parents had already manifested IBD symptoms. Of the 9 children over age 20, 6 (67%) have developed IBD (5 CD and 1 UC). Of 11 children who were conceived when only 1 parent Table 4. Types of Inflammatory Bowel Disease in Parents and Children Parents UC-UC (1) CD-UC (2) CD-CD (3) Children [present study] Children (in the literature)

UC CD UC CD

1 2 0 0

2 3 1 0

0 4 0 2

June

IBD IN OFFSPRING

1991

Table 5. Smoking Type of IBD

Never smoked Began smoking before onset of IBD symptoms Began smoking after onset of IBD symptoms Cannot remember when began smoking in relation to onset of IBD symptoms

23 CD

15 UC

7

5

7

5

1

1

8

4

had IBD symptoms, 6 are older than 20 years; of them, 3 (50%) have developed IBD (2 CD and 1 UC). Finally, of the 9 children conceived at a time when neither parent had yet developed IBD, 6 have reached at least age 20; 3 of them (50%) have IBD (2 CD and 1 UC). There are currently 7 grandchildren born to the 23 children reported in this study. Only one (C2) has had children who have also developed IBD (2 of 3 with CD). It must be noted that almost all of these grandchildren are age 20 or below. Five of the 38 spouses have developed neoplasms. In A3, the husband died at the age of 58 of lymphocytic lymphoma and his wife died from hepatic cancer at the age of 49. The wife in C2 had colon cancer 16 years after she was diagnosed with UC. The husband in C3 was concomitantly found to have carcinoma of the esophagus and Barrett’s esophagus 1 year after he experienced symptoms of, but 9 years before he was diagnosed with, CD. In C5 the wife had carcinoma of the ileum 27 years after she was diagnosed with CD. There was no significant difference in smoking rates between CD and UC patients in all three groups studied. Sixteen of the 23 patients with CD (70%) have a history of smoking. Of the a who could remember exactly when they started smoking, only 1 (6%) began smoking after the onset of symptoms of IBD. Of the 15 patients with UC, 10 (67%) had a smoking history. Of these, 5 (50%) could recall initiating smoking before and 1 (10%) remembers beginning to smoke after the onset of disease (Table 5).

Discussion We have studied 19 married couples with IBD and divided them into three groups based on when they developed IBD relative to the date of their marriage. In those groups in which one (group B) or both (group C) spouses developed IBD after marriage, there was a remarkably similar mean interval from time of exposure to a spouse affected with IBD to development of IBD in the second spouse (6.4 and 6.6

OF COUPLES WITH IBD

1641

years in groups B and C, respectively), although the range was wide (1-16 years). Although the initial spouse had CD in 6 of 14 patients, the second spouse developed CD in 10 of 14. The numbers are too small to conclude that there is an increased risk of CD developing in the second spouse compared with UC. We found a high rate of IBD (36%) in the offspring of these couples. Descriptions of the 15 husband-wife include couples with IBD previously reported (41-51) mention of 6 children born to 4 couples, 3 of whom (50%) developed IBD (42,44,47). This prevalence is higher than in those reported series in which only 1 parent had IBD (8). Although there was no apparent proclivity or concordance for one or another particular form of IBD among these 19 married couples with IBD, 9 of their 12 affected children (75%) have CD. Moreover, when both parents had CD, all 4 affected children developed CD. This is the same pattern previously reported in 2 other couples concordant for CD who had 2 children, both of whom subsequently developed CD (44,47). The development of IBD after marriage in the second spouse of 14 couples (groups B and C) suggests either a chance occurrence or an environmental factor in the pathogenesis of disease in this patient population. In the United States, the prevalence of CD and UC is usually cited in the literature as 40 of 100,000 and 79.9 of 100,000 of the population, respectively (11). Assuming that the population base of our practice is approximately 6 million, the chance that 2 randomly paired individuals will both develop either disease is then 120 of 100,000 (2) or 1.44 of 1 million, making it unlikely that 14 couples with IBD from this population would be married by chance alone. This is consistent with a report by Lobo et al. from the United Kingdom noting a greater occurrence of married couples with CD than would be expected by chance alone (49). On the other hand, our observations could be caused by chance alone, considering the uncertainties of IBD prevalence. It should also be emphasized that in our practice population 70% of patients are Jewish and that 87% of the 19 pairs were Jewish. The assortative mating pattern may therefore be positive, because Jewish patients tend to marry each other more frequently than chance alone would indicate. Regardless of whether the occurrence of IBD in these couples is random, our study has yielded four new observations: the increased frequency in offspring when both parents have IBD, the proclivity toward CD in offspring, especially when parents are concordant for CD, the virtually identical mean interval between spouse occurrence in groups B and C, and the atypically older age of onset in the second spouse in groups B and C. In interpreting our data, we find it impossible to

1642

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GASTROENTEROLOGY

ET AL.

differentiate genetics from environment in the causation of IBD. It may be that a genetic component links the 19 married couples studied and accounts for the high rate of IBD in offspring, but we have no evidence of consanguinity or other genetic similarities to support this possibility; also, the inflated rate of IBD in children could just as easily be accounted for by a shared environmental exposure. If the environmental factor is an infectious agent, it would have to be one with a long latency period (6.4 years in group B and 6.8 years in group C). A shared noninfectious environmental component such as water supply, diet, or lifestyle can not be excluded. We did not observe a high rate of concordance for the type of IBD in spouses, suggesting that either multiple environmental agents are involved or that the type of IBD depends on the size of the “inoculum” or the genetic predisposition of the host. This model is consistent with Lewkonia and McConnell’s theory of polygenic inheritance of IBD, in which “CD and UC may be the same diseases with a quantitatively related genetic base. Crohn’s disease would be the result in people with a large concentration of genes, while fewer of the relevant genes would result in UC. . . . it is likely that genetically determined responses are of major importance in explaining the individual susceptibility to IBD” (1). Our observation of CD begetting CD (Table 4) is consistent with this polygenic theory. Our series bring to 34 the number of case reports of IBD in husband-wife couples reported in the literature.* It is possible that this series represents an underestimate of the numbers of husbands and wives with IBD, because a second spouse may have developed the disease and there is a delay in reporting this occurrence to our office. This occurred in case 21 noted below, in which the husband with CD moved to Florida, married a woman who had UC, and did not report this to us until he returned 12 years later for another reevaluation. Obviously, these numbers are still too small to permit us to draw any firm conclusion regarding the etiology of IBD. Data on more couples must first be collected and analyzed before we can make any definitive statements. To accomplish this, we are planning to develop a national registry of IBD couples using the Crohn’s and Colitis Foundation of America (formerly the National Foundation for Ileitis and Colitis).

*After this report was compiled, a 20th and 2lst case occurred in our practice. In the 20th case the second spouse of a woman with proctosigmoiditis developed UC 4 years after marriage. The couple has no children. In the 21st case, the husband has CD and the wife has UC; both were affected before marriage. They have 2 children, ages 7 and 11, with no evidence of IBD as yet.

Vol. 100, No. 6

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Received May 14,1989. Accepted November 19,199O. Address requests for reprints to: Daniel H. Present, M.D., 12 East 86th Street, New York, New York 10028.

Frequency of inflammatory bowel disease in offspring of couples both presenting with inflammatory bowel disease.

A private practice was surveyed for prevalence of inflammatory bowel disease (IBD) in husband-wife partners and in their children. Among approximately...
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