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Hirschsprung's disease in Oman
Hirschsprung’s
Disease in Oman
By A. Rajab, N.V. Freeman, London, l The incidence of Hirschsprung’s disease IHD) was studied retrospectively in Oman using hospital-based data. In Oman there is a single pediatric surgery unit where a register has been kept from 1989 to 1994, and because all cases are referred to this unit, a national survey could be carried out. There were 85 children with HD born between 1989 and 1994, and during this period there were 261,000 livebirths among Omani nationals. The population frequency in Oman is 1 in 3,070 (0.3/1,000). Eighty percent of cases presented in the first 6 months. The incidence in different regions and within different tribes of Oman was also studied. The highest frequency (1 in 1,800) is in the North Sharqiya region. There was not a significant seasonal influence in spite of the very high temperatures seen in the desert summer. The ratio of male to female cases was 2.9:1 overall, but less for longer-segment involvement. The consanguinity rate (first and second cousins) was 76%, which is higher than the level of consanguinity in the Omani population. Down’s syndrome was observed in nine cases (II%), and a variety of other malformations were seen, including piebaldism, deafness, and HD in two sibships. Copyright o 7997 by W.3. Saunders Company
INDEX genetics,
WORDS: Hirschsprung’s consanguinity.
disease,
Oman,
incidence,
H
IRSCHSPRUNG’S DISEASE (aganglionosis of the colon; HD) is a disorder characterized by the absence of ganglion cells in the myenteric plexuses of the distal intestinal tract. The population incidence usually reported in Western countries is about 1 in 5,000 live births, with an increased male predisposition especially for the short-segment disease.’ The incidence in Oman and other Gulf states has not been previously investigated. The Sultanate of Oman is located in the South East comer of the Arabian penninsula. It covers 212,000 square km and has a resident population of 1.5 million excluding the expatriate population. The terrain of this country is varied with subtropical areas in the south, large areas of desert in the center, and high mountain ranges in the north. The country has remained isolated, and development of specialized medical services only took place in this present generation when the revenue from oil allowed greater prosperity. There is a high proportion of
From the Departments of Child Health and Pediatric Surgep), Royal Hospital, Muscat, Oman, and the Deparfmeni of Medical Getzetics, St Georges Hospital Medical School, London, England. Address reprint requests to Michael A Patton, MD, Department of Medical Genetics, St Georges Hospital Medical School, Cranmer Terrace, London SW1 7 ORE, England. Copyright o 1997 by WB. Saunders Cornpan) 0022-3468/97/3205-0016$03.00/O
724
and M.A. Patton
England
consanguineous marriages similar to other Gulf states, and the country has a high humidity and temperature especially during the summer months. HD was believed to have a multifactorial basis with both genetic and environmental factors playing a part in the aetiology,2.3 but now there is a clearer understanding of the heterogeneity underlying the disorder. It has long been associated with Down’s syndrome.*.4 Recent genetic studies have defined some of the genetic predispositions to this syndrome with the discovery of specific predisposing genes on chromosomes 10 and 13.5.6The inital studies identifying the predisposing gene on chromosome 13 came from studying the isolated and inbred Mennonite community, and it is possible that studies of similar isolated populations may be helpful in the identification of other predisposing genes. One of the environmental factors that has been determined as a causative factor of colonic aganglionsis7,* is hyperthermia (raised body temperature during pyrexial illness or sauna) in the early stages of pregnancy. It was postulated that the high environmental temperatures reached in Oman during desert summer could have similar teratogenic effects. MATERIALS
AND
METHODS
In the health care system in Oman all patients with a suspicion of HD are referred to a single unit (Royal Hospital. Pediatric Surgical Unit) for investigation and treatment. There are no other facilities for dealing with these children in Oman. It therefore offers the possibility of complete ascertainment within a single country. A complete computerized database has been maintained in the Royal Hospital Pediatric Surgical unit since 1989, and this registry was used to locate the patients. Case files of all patients seen at the unit with a possible diagnosis of HD born during the 6 years (1989 through 1994) were then reviewed. Results of the rectal biopsies were also reviewed, and patients with doubtful or negative biopsy results have been excluded from the study (25 cases) as well as non-Omani (expatriate) children (four cases). Data for analysis included detaiis of names (first, father, grandfather. and tribal), age, sex, and residence. Results of the colonic suction and postoperative biopsy results, dates and types of surgical procedures, and associated anomahes were recorded. The estimated date of conception was calculated in the 85 chtldren with HD. Seasonal variation in date of birth was analyzed to determine if there was a higher incidence of patients born after the hot season. Analysis of the incidence of HD in different tribes and in different regions of Oman was carried out to detect any possible geographical or genetic clustering. Data have been collected on maternal and paternal age. birth order, number of siblings, and consangumity where possible.
RESULTS
During a period of 6 years (1989 through 1994) 85 babies with a diagnosis of HD were born in a population of 261,000 live births among Omani nationals, which Journal
of Pediatric
Surgery,
Vol 32, No 5 (May),
1997. pp 724.727
HIRSCHSPRUNG’S
725
DISEASE
makes the frequency of HD in Oman 1 in 3,070 (0.3/ 1,000). By way of comparison, the incidence of HD in the expatriate population in the same period of time was 1 in 4,000 (4 cases among 16,000 deliveries from 1989 through 1994). There were significant variations in the birth incidence of HD in different regions (Fig 1). The capital area with a population of 335,000 had a frequency of 1 in 4,200, while the North Batna Region with a population of 285,000 had a frequency 1 in 2,000. The highest incidence (1 in 1,800 live births or 0.55/1,000) was observed in the Northeastern Region (North Sharqiya). Most cases (61%) of HD presented in the first month of life, and 8 1% had presented by 6 months of age. However, there were a few cases (7%) that presented between 2 and 5 years. A positive family history was recorded in six families out of 85 cases (7%). In two families there was a history of multiple siblings affected with piebaldism, deafness, and long-segment HD. In these two families all (eight) affected children have died. There were also three families with an additional sibling affected and one family with a first cousin affected. The consanguinity rate (ie, the proportion of first and second cousin marriages in the population) is high in many Gulf states but had not been documented in Oman. However, a study of 7,101 births from seven obstetric units in Oman in 1994 gave a consanguinity rate of 32.8% (Rajab A, unpublished data). The consanguinity rate in HD, when it was recorded in the case notes, was 75%. This is roughly twice that in the general population.
Table 1. Incidence HD cases per tribe No.oftrrbesHDobserved NOTE. shown. tribe.
The Most
of HD in Tribes 2
3
4
7
5
1
of HD among
Omani
1 40
distribution of the tribes
of 85 cases have three
or fewer
affected
Anomalies
in HD Cases No.
Associated
of
CASTS
Anomalies
Down’s syndrome Renal tract anomalies Included Posterior urethral valves
9
Single kidney Gastrointestinal
2 anomalies
Microcephaly and short Mental retardation Bronchrectasrs Others Total
lnudence
11% 5%
2
included
2% 1
Gut malrotations Meckel’s diverticulum Piebaldism and deafness
incidence of Hirschsprung’s disease in Oman. C, Batna; SB, South Batna; DR, Dhahira; DK, Dakhliya; SS, South Sharqiya; DU, Dhofar; W, Wusta.
tribes
individuals
IS per
There are approximately 600 tribes in Oman and, because the family name and tribal name is recorded in the hospital record, it is possible to look at the distribution of HD within tribes. Only 54 tribal names featured in the cases of HD and about one fifth of all cases (18.8%) occurred in just two tribes. In most cases (81%) there were three or fewer affected individuals in the tribe (Table 1). The extent of the aganglionic segment was recorded for all patients studied. Total aganglionosis occured in four patients (3M:lF), long segment involvement occurred in seven patients (3M:4F), recta-sigmoid involvement occurred in 53 patients (45M:8F). and there was short-segment involvement in 21 patients (12M:9F). Six children in the series with aganglionosis had problems in the neonatal period but subsequently have been defecating satisfactorily at the age of 1 to 3 years without surgical intervention. The records identified other congenital anomalies in 23 patients (27%). The most frequent anomaly was Down’s syndrome which was found in nine patients (11%). renal tract anomalies were found in 5%, and gastrointestinal anomalies in 2%. Two families had a combination of piebaldism, deafness, and HD, which is recognized as a variant of Waardenburg’s syndrome (Table 2). The effect of birth order was studied using the method of Haldane and Smithgs1oin which details of the complete sibship were available. Full pedigrees were obtained in all patients presenting after 1994, and in the data collected retrospectively between 1989 and 1994 there were 10 full pedigrees. The observed mean birth order (6A = 268) lies well within the standard deviation of the theoretical mean Table 2. Associated
Fig 1. Regional Capital: NB, North NS, Noth Sharqiya;
12 1
stature
1 2 1 1 1 3 23
2% 2% 1% 3%
726
RAJAB,
Table 3. Month JX
Control deliveries HD born (%) No. of HD cases
1%)
Feb
March
8.6
7.4
7.1
10.5
9.4 8
9
of Birth
With
AND
PATTON
HD
JUIX
July
Aw
Sept
Ott
NOV
7
6.9
7.6
8.1
9.6
9.3
9.3
9.3
9.6
15.3
8.2
5.9
9.4
7
9.4
4.7
7
9.4
3.5
13
7
5
8
6
8
4
6
8
3
NOTE. Dates of birth of HD cases compared with seasonal March to August (hot months) with Sept to Feb (cold months),
Aprd
for Patients
FREEMAN,
variation of birthrates m general ie, 55.2% to 44.8% (P > .lO).
(231 + 73.8) indicating that there is no significant effect from birth order rank. The parental age was also studied. The mean maternal age was of HD patients was 26.4 + 7.23, and the mean paternal age was 34.5 t 10.8. No comparable published figures are available from the general population in Oman, however, a survey of 100 couples questioned in antenatal clinics showed a mean maternal age of 23.2 ? 5.6 and a mean paternal age of 32.6 ? 8.9. This excludes a significant paternal age effect (P = .l), but suggests that the mean age of the mothers of HD patients is significantly greater than the mean maternal age of the general population (P < ,001). Because the temperature in Oman reaches 48°C and humidity 60% to 80% during tropical desert summer, seasonal incidence of HD was studied. In 85 cases of HD there was no significant difference in the proportion of cases born in the hot months (March through August) as opposed to the cold months (September through February, Table 3). DISCUSSION
In Britain and North America most textbooks quote the frequency of Hirschprung’s disease to be 1 in 5,000 live births. A study from Baltimore showed an overall incidence of 1 in 5,376 in a hospital-based series, and found a higher rate among nonwhite boys.” Another study from Vancouvefi found an incidence of 1 in 4,417 in a cohort ascertained throughout British Columbia. Studies outside North America have shown similar frequencies. A study by Russell et all2 looking at 1.5 million consecutive births in Denmark found a frequency of 1 in 7,165 live births, and in Japan, Ikeda and Goto13 collected data on 1,628 patients with HD in a national study. They found the incidence to be 1 in 4,697. The incidence of HD in Oman from this study is 1 in 3,070 (0.3/1,000). This frequency is higher than the previously cited studies, and within parts of Oman the frequency was considerably greater than in the Western studies. There is no comparable data available from other Middle Eastern countries. The relatively late presentation of HD in some children may reflect cultural differences. Many mothers do not stay in the hospital after the birth of their child because they have other children at home. and many live in remote areas. HD may present later in life, and it is possible that this study may underestimate the incidence
population
of Oman.
Comparison
DeC
of proportion
m
if there are further cases in the cohort from 1989 through 1994 who present later. It is of interest that an adult presentation has been reported in the medical literature from Saudi Arabia.14 This study confirmed a greater male to female ratio overall (2.9:1), but in long-segment Hirschprung’s disease the sex ratio is reduced. This has been observed in other studies. In Goldberg’s study” the overall sex ratio was 4.32: 1 and in Russell studyI it was 4.1:1 for short-segment and 2.4: 1 in long-segment disease. Maternal hyperthermia in early stages of pregnancy has been shown to have teratogenic effects, and is believed to be an etiological factor of HD.15 It is difficult to separate the teratogenic effects of infective pathogens when the pyrexial occurs with infection, but the ambient temperature in a sauna has also been suggested to be teratogenic. Therefore, because the summer temperature in Oman makes it one of the hottest places in the world, the study investigated whether there was any seasonal influence on HD. However we were unable to show that conception during the hot season influences the frequency of HD in Oman. It is likely that genetic rather than environmental factors are responsible for this increase because the frequency in the expatriate population was not significantly increased. The previous epidemiological studies analyzing the effect of birth order in HD have given inconsistent results. In Goldberg’s study from Baltimore” there was an increased incidence in the first-born children, however other studies did not confirm thiss2.14The analysis of the data in our study showed that there is no significant birth-order effect or parental age effect. The mean paternal age is greater than the mean maternal age in both the HD population and the control group, but this reflects the cultural tradition of women to marrying earlier than men. In 27% of children with HD other congenital defects have been found. The most common association was with Down’s syndrome. This is well-recognized association. Some of the other defects, such as malrotation, are likely to be secondary to the neurogenic abnormality in the bowel, and others may be coincidental. However this is not the case with the finding of two families with piebaldism, deafness, and HD occurring in four siblings. This association is one of the recognized syndromes that
HIRSCHSPRUNG’S
DISEASE
727
has been described with HD,16 and recent studies reported by Attie et all7 showed that in a similar child of consanguineous Tunisian parents there was a missense mutation in exon 2 of the endothelin B receptor gene. Although the children in these families in Oman have since died, molecular studies are being undertaken. Marriage still tends to take place within tribes. which are geographically based. This probably accounts for the regional differences in the frequency within the country. The highest incidence is in the North Sharqiyah region where the frequency is 1 in 1,800 live births. When the distribution of cases is compared with tribal name it is found that half of the cases are single cases within the tribe. In the tribes were recurrence has occurred it is usually within the immediate family. There have been various patterns of inheritance suggested for HD. The initial suggestion was that this is a multifactorial condition with a greater male frequency,2 but it was soon noted that it was heterogeneous. The occurrence of both autosomal dominant and autosomal recessive inheritance was suggested from the reported kindreds, and the condition was also found to be associated with Down’s syndrome and deletion of chromosome 13q22.‘*‘*,‘9 These findings have led to research that identified
mutations in the endothelin B receptor on chromosome 13.‘j Because this discovery was initially made in an inbred Mennonite community it appears that this gene is likely to be significant in other families with siblings affected, and that it is a dose-sensitive mutation with a greater likelihood of homozygotes developing HD. In the Mennonite families heterozygotes had a 21% chance of manifesting HD and homozygotes a 74% chance of manifesting HD. Further research also identified a deletion of the pericentromeric region of chromosome 10 in total aganglionosis, and from this genetic study mutations in the ret oncogene were identified, this oncogene surprisingly produced HD rather than the medullary cell carcinomas initially identified with this gene.5 The consanguinity as expressed by the proportion of first and second cousin marriages compared with the background population is considerably increased. Thus, the main reason for the increase in HD in Oman is likely to be because of the increasing prevalance of recessive mutations. Some of these may be of low penetrance and therefore formal segregation analysis does not confirm the classical segregation ratio of autosomal recessive inheritance. If there are further recessive mutations to be identified it is likely the detailed study of isolated inbred populations such as this will be fruitful.
REFERENCES 1. Badner JA, Sieber WK. Garver KL. et al: A Genetic study of Hirschprung disease. Am J Hum Genet 46:568-580. 1990 2. Bodtan M, Carter CO: A family study of Hirschsprung’s disease. J Med Genet 26:261-277,1963 3. Passarge E: The genetics of Hirschsprung’s disease: Evidence for heterogeneous etiology and a study of sixty three families. N Engl J Med 276:138-143, 1967 4. Spouge D, Baird PA: Hirschsprungs disease in a large birth cohort. Teratology 32:171-177. 1985 5. Lyonnet S, Bolmo A. Pelet A, et al: A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nature Genet 4:346-348, 1994 6. Puffenberger EG, Hosoda K, Washington SS, et al: A mtssense mutatton of the endothelin-B receptor gene in multtgemc Hirschsprung’s disease. Cell 79: 1257-1266, 1994 7. Winter RM, Baraitser M: Multiple Congenital Anomalies: Adiagnostic Compendium. London, Chapman and Hall, 1991, pp 384-385 8. Larson LT, Okmian L, Kristafferson UN: No correlation between hypertermia during pregnancy and Hirschprung’s disease in the offspring. (Letter) Am J Med Genet 32:260-261. 1989 9. Haldane JBS, Smith CAB: A simple exact test for birth order effect. Ann Eugen 14: 117- 124.1947 10. Emery AEH: Methodology in Medical Genetics. An Introduction to Statistical Methods. Edinburgh, Churchill Livingstone, 1976, pp 108-111
11. Goldberg EL: An epidemiological study of Hirschsprung’s disease. Int J Epidemiol 13:479-485. 1984 12. Russell MB. Russell CA, Niebuhr E: An epidemiological study of Hirschsprung’s disease and additional anomalies. Acta Paed 83.6871,1994 13. Ikeda K, Goto S: Diagnosis and treatment of Hirschpnmg’s disease in Japan, Ann Surg 4:400-405. 1994 14. Al-Amri SM; Makajoula D, Al-Rasheed RS, et al: Hirschprung’s disease m adult. Saudi Med J 17.82-85. 1996 15. SmithMSR. Edwards MJ, Upfold JB: The effect of hyperthermia on the fetus. Dev Med Child Neurol28:803-813, 1986 16. Shah KN, Dalal SJ. Desai MP, et al: White forelock, pigmentary disorders of the irides and long segment Hirschsprung disease: Possible variant of Waardenburg disease. J Pediatr 99:432-435. 198 1 17. Attie T, Till M, Amiel J. et al: Endothelin B receptor gene mutation in a consangineous family with Waardenberg-Hirschsprung Disease: A possible variant of Waardenberg disease. J Pediatr 99:432435. 1981 18. Lamont MA. Fitchett M. Dennis NR: Interstitial deletion of distal 13q associated with Hirschsprung’s disease. J Med Genet 26: 100-104, 1979 19. Bottam A, Xie Y, Binkert F, et al: A case of Hirschprung disease with a chromosome 13 microdeletion, de1(13)cq32.3q33.2): Potential mapping of one disease locus. Hum Genet 87:748-750. 1991
Disease in Oman
By A. Rajab, N.V. Freeman, London, l The incidence of Hirschsprung’s disease IHD) was studied retrospectively in Oman using hospital-based data. In Oman there is a single pediatric surgery unit where a register has been kept from 1989 to 1994, and because all cases are referred to this unit, a national survey could be carried out. There were 85 children with HD born between 1989 and 1994, and during this period there were 261,000 livebirths among Omani nationals. The population frequency in Oman is 1 in 3,070 (0.3/1,000). Eighty percent of cases presented in the first 6 months. The incidence in different regions and within different tribes of Oman was also studied. The highest frequency (1 in 1,800) is in the North Sharqiya region. There was not a significant seasonal influence in spite of the very high temperatures seen in the desert summer. The ratio of male to female cases was 2.9:1 overall, but less for longer-segment involvement. The consanguinity rate (first and second cousins) was 76%, which is higher than the level of consanguinity in the Omani population. Down’s syndrome was observed in nine cases (II%), and a variety of other malformations were seen, including piebaldism, deafness, and HD in two sibships. Copyright o 7997 by W.3. Saunders Company
INDEX genetics,
WORDS: Hirschsprung’s consanguinity.
disease,
Oman,
incidence,
H
IRSCHSPRUNG’S DISEASE (aganglionosis of the colon; HD) is a disorder characterized by the absence of ganglion cells in the myenteric plexuses of the distal intestinal tract. The population incidence usually reported in Western countries is about 1 in 5,000 live births, with an increased male predisposition especially for the short-segment disease.’ The incidence in Oman and other Gulf states has not been previously investigated. The Sultanate of Oman is located in the South East comer of the Arabian penninsula. It covers 212,000 square km and has a resident population of 1.5 million excluding the expatriate population. The terrain of this country is varied with subtropical areas in the south, large areas of desert in the center, and high mountain ranges in the north. The country has remained isolated, and development of specialized medical services only took place in this present generation when the revenue from oil allowed greater prosperity. There is a high proportion of
From the Departments of Child Health and Pediatric Surgep), Royal Hospital, Muscat, Oman, and the Deparfmeni of Medical Getzetics, St Georges Hospital Medical School, London, England. Address reprint requests to Michael A Patton, MD, Department of Medical Genetics, St Georges Hospital Medical School, Cranmer Terrace, London SW1 7 ORE, England. Copyright o 1997 by WB. Saunders Cornpan) 0022-3468/97/3205-0016$03.00/O
724
and M.A. Patton
England
consanguineous marriages similar to other Gulf states, and the country has a high humidity and temperature especially during the summer months. HD was believed to have a multifactorial basis with both genetic and environmental factors playing a part in the aetiology,2.3 but now there is a clearer understanding of the heterogeneity underlying the disorder. It has long been associated with Down’s syndrome.*.4 Recent genetic studies have defined some of the genetic predispositions to this syndrome with the discovery of specific predisposing genes on chromosomes 10 and 13.5.6The inital studies identifying the predisposing gene on chromosome 13 came from studying the isolated and inbred Mennonite community, and it is possible that studies of similar isolated populations may be helpful in the identification of other predisposing genes. One of the environmental factors that has been determined as a causative factor of colonic aganglionsis7,* is hyperthermia (raised body temperature during pyrexial illness or sauna) in the early stages of pregnancy. It was postulated that the high environmental temperatures reached in Oman during desert summer could have similar teratogenic effects. MATERIALS
AND
METHODS
In the health care system in Oman all patients with a suspicion of HD are referred to a single unit (Royal Hospital. Pediatric Surgical Unit) for investigation and treatment. There are no other facilities for dealing with these children in Oman. It therefore offers the possibility of complete ascertainment within a single country. A complete computerized database has been maintained in the Royal Hospital Pediatric Surgical unit since 1989, and this registry was used to locate the patients. Case files of all patients seen at the unit with a possible diagnosis of HD born during the 6 years (1989 through 1994) were then reviewed. Results of the rectal biopsies were also reviewed, and patients with doubtful or negative biopsy results have been excluded from the study (25 cases) as well as non-Omani (expatriate) children (four cases). Data for analysis included detaiis of names (first, father, grandfather. and tribal), age, sex, and residence. Results of the colonic suction and postoperative biopsy results, dates and types of surgical procedures, and associated anomahes were recorded. The estimated date of conception was calculated in the 85 chtldren with HD. Seasonal variation in date of birth was analyzed to determine if there was a higher incidence of patients born after the hot season. Analysis of the incidence of HD in different tribes and in different regions of Oman was carried out to detect any possible geographical or genetic clustering. Data have been collected on maternal and paternal age. birth order, number of siblings, and consangumity where possible.
RESULTS
During a period of 6 years (1989 through 1994) 85 babies with a diagnosis of HD were born in a population of 261,000 live births among Omani nationals, which Journal
of Pediatric
Surgery,
Vol 32, No 5 (May),
1997. pp 724.727
HIRSCHSPRUNG’S
725
DISEASE
makes the frequency of HD in Oman 1 in 3,070 (0.3/ 1,000). By way of comparison, the incidence of HD in the expatriate population in the same period of time was 1 in 4,000 (4 cases among 16,000 deliveries from 1989 through 1994). There were significant variations in the birth incidence of HD in different regions (Fig 1). The capital area with a population of 335,000 had a frequency of 1 in 4,200, while the North Batna Region with a population of 285,000 had a frequency 1 in 2,000. The highest incidence (1 in 1,800 live births or 0.55/1,000) was observed in the Northeastern Region (North Sharqiya). Most cases (61%) of HD presented in the first month of life, and 8 1% had presented by 6 months of age. However, there were a few cases (7%) that presented between 2 and 5 years. A positive family history was recorded in six families out of 85 cases (7%). In two families there was a history of multiple siblings affected with piebaldism, deafness, and long-segment HD. In these two families all (eight) affected children have died. There were also three families with an additional sibling affected and one family with a first cousin affected. The consanguinity rate (ie, the proportion of first and second cousin marriages in the population) is high in many Gulf states but had not been documented in Oman. However, a study of 7,101 births from seven obstetric units in Oman in 1994 gave a consanguinity rate of 32.8% (Rajab A, unpublished data). The consanguinity rate in HD, when it was recorded in the case notes, was 75%. This is roughly twice that in the general population.
Table 1. Incidence HD cases per tribe No.oftrrbesHDobserved NOTE. shown. tribe.
The Most
of HD in Tribes 2
3
4
7
5
1
of HD among
Omani
1 40
distribution of the tribes
of 85 cases have three
or fewer
affected
Anomalies
in HD Cases No.
Associated
of
CASTS
Anomalies
Down’s syndrome Renal tract anomalies Included Posterior urethral valves
9
Single kidney Gastrointestinal
2 anomalies
Microcephaly and short Mental retardation Bronchrectasrs Others Total
lnudence
11% 5%
2
included
2% 1
Gut malrotations Meckel’s diverticulum Piebaldism and deafness
incidence of Hirschsprung’s disease in Oman. C, Batna; SB, South Batna; DR, Dhahira; DK, Dakhliya; SS, South Sharqiya; DU, Dhofar; W, Wusta.
tribes
individuals
IS per
There are approximately 600 tribes in Oman and, because the family name and tribal name is recorded in the hospital record, it is possible to look at the distribution of HD within tribes. Only 54 tribal names featured in the cases of HD and about one fifth of all cases (18.8%) occurred in just two tribes. In most cases (81%) there were three or fewer affected individuals in the tribe (Table 1). The extent of the aganglionic segment was recorded for all patients studied. Total aganglionosis occured in four patients (3M:lF), long segment involvement occurred in seven patients (3M:4F), recta-sigmoid involvement occurred in 53 patients (45M:8F). and there was short-segment involvement in 21 patients (12M:9F). Six children in the series with aganglionosis had problems in the neonatal period but subsequently have been defecating satisfactorily at the age of 1 to 3 years without surgical intervention. The records identified other congenital anomalies in 23 patients (27%). The most frequent anomaly was Down’s syndrome which was found in nine patients (11%). renal tract anomalies were found in 5%, and gastrointestinal anomalies in 2%. Two families had a combination of piebaldism, deafness, and HD, which is recognized as a variant of Waardenburg’s syndrome (Table 2). The effect of birth order was studied using the method of Haldane and Smithgs1oin which details of the complete sibship were available. Full pedigrees were obtained in all patients presenting after 1994, and in the data collected retrospectively between 1989 and 1994 there were 10 full pedigrees. The observed mean birth order (6A = 268) lies well within the standard deviation of the theoretical mean Table 2. Associated
Fig 1. Regional Capital: NB, North NS, Noth Sharqiya;
12 1
stature
1 2 1 1 1 3 23
2% 2% 1% 3%
726
RAJAB,
Table 3. Month JX
Control deliveries HD born (%) No. of HD cases
1%)
Feb
March
8.6
7.4
7.1
10.5
9.4 8
9
of Birth
With
AND
PATTON
HD
JUIX
July
Aw
Sept
Ott
NOV
7
6.9
7.6
8.1
9.6
9.3
9.3
9.3
9.6
15.3
8.2
5.9
9.4
7
9.4
4.7
7
9.4
3.5
13
7
5
8
6
8
4
6
8
3
NOTE. Dates of birth of HD cases compared with seasonal March to August (hot months) with Sept to Feb (cold months),
Aprd
for Patients
FREEMAN,
variation of birthrates m general ie, 55.2% to 44.8% (P > .lO).
(231 + 73.8) indicating that there is no significant effect from birth order rank. The parental age was also studied. The mean maternal age was of HD patients was 26.4 + 7.23, and the mean paternal age was 34.5 t 10.8. No comparable published figures are available from the general population in Oman, however, a survey of 100 couples questioned in antenatal clinics showed a mean maternal age of 23.2 ? 5.6 and a mean paternal age of 32.6 ? 8.9. This excludes a significant paternal age effect (P = .l), but suggests that the mean age of the mothers of HD patients is significantly greater than the mean maternal age of the general population (P < ,001). Because the temperature in Oman reaches 48°C and humidity 60% to 80% during tropical desert summer, seasonal incidence of HD was studied. In 85 cases of HD there was no significant difference in the proportion of cases born in the hot months (March through August) as opposed to the cold months (September through February, Table 3). DISCUSSION
In Britain and North America most textbooks quote the frequency of Hirschprung’s disease to be 1 in 5,000 live births. A study from Baltimore showed an overall incidence of 1 in 5,376 in a hospital-based series, and found a higher rate among nonwhite boys.” Another study from Vancouvefi found an incidence of 1 in 4,417 in a cohort ascertained throughout British Columbia. Studies outside North America have shown similar frequencies. A study by Russell et all2 looking at 1.5 million consecutive births in Denmark found a frequency of 1 in 7,165 live births, and in Japan, Ikeda and Goto13 collected data on 1,628 patients with HD in a national study. They found the incidence to be 1 in 4,697. The incidence of HD in Oman from this study is 1 in 3,070 (0.3/1,000). This frequency is higher than the previously cited studies, and within parts of Oman the frequency was considerably greater than in the Western studies. There is no comparable data available from other Middle Eastern countries. The relatively late presentation of HD in some children may reflect cultural differences. Many mothers do not stay in the hospital after the birth of their child because they have other children at home. and many live in remote areas. HD may present later in life, and it is possible that this study may underestimate the incidence
population
of Oman.
Comparison
DeC
of proportion
m
if there are further cases in the cohort from 1989 through 1994 who present later. It is of interest that an adult presentation has been reported in the medical literature from Saudi Arabia.14 This study confirmed a greater male to female ratio overall (2.9:1), but in long-segment Hirschprung’s disease the sex ratio is reduced. This has been observed in other studies. In Goldberg’s study” the overall sex ratio was 4.32: 1 and in Russell studyI it was 4.1:1 for short-segment and 2.4: 1 in long-segment disease. Maternal hyperthermia in early stages of pregnancy has been shown to have teratogenic effects, and is believed to be an etiological factor of HD.15 It is difficult to separate the teratogenic effects of infective pathogens when the pyrexial occurs with infection, but the ambient temperature in a sauna has also been suggested to be teratogenic. Therefore, because the summer temperature in Oman makes it one of the hottest places in the world, the study investigated whether there was any seasonal influence on HD. However we were unable to show that conception during the hot season influences the frequency of HD in Oman. It is likely that genetic rather than environmental factors are responsible for this increase because the frequency in the expatriate population was not significantly increased. The previous epidemiological studies analyzing the effect of birth order in HD have given inconsistent results. In Goldberg’s study from Baltimore” there was an increased incidence in the first-born children, however other studies did not confirm thiss2.14The analysis of the data in our study showed that there is no significant birth-order effect or parental age effect. The mean paternal age is greater than the mean maternal age in both the HD population and the control group, but this reflects the cultural tradition of women to marrying earlier than men. In 27% of children with HD other congenital defects have been found. The most common association was with Down’s syndrome. This is well-recognized association. Some of the other defects, such as malrotation, are likely to be secondary to the neurogenic abnormality in the bowel, and others may be coincidental. However this is not the case with the finding of two families with piebaldism, deafness, and HD occurring in four siblings. This association is one of the recognized syndromes that
HIRSCHSPRUNG’S
DISEASE
727
has been described with HD,16 and recent studies reported by Attie et all7 showed that in a similar child of consanguineous Tunisian parents there was a missense mutation in exon 2 of the endothelin B receptor gene. Although the children in these families in Oman have since died, molecular studies are being undertaken. Marriage still tends to take place within tribes. which are geographically based. This probably accounts for the regional differences in the frequency within the country. The highest incidence is in the North Sharqiyah region where the frequency is 1 in 1,800 live births. When the distribution of cases is compared with tribal name it is found that half of the cases are single cases within the tribe. In the tribes were recurrence has occurred it is usually within the immediate family. There have been various patterns of inheritance suggested for HD. The initial suggestion was that this is a multifactorial condition with a greater male frequency,2 but it was soon noted that it was heterogeneous. The occurrence of both autosomal dominant and autosomal recessive inheritance was suggested from the reported kindreds, and the condition was also found to be associated with Down’s syndrome and deletion of chromosome 13q22.‘*‘*,‘9 These findings have led to research that identified
mutations in the endothelin B receptor on chromosome 13.‘j Because this discovery was initially made in an inbred Mennonite community it appears that this gene is likely to be significant in other families with siblings affected, and that it is a dose-sensitive mutation with a greater likelihood of homozygotes developing HD. In the Mennonite families heterozygotes had a 21% chance of manifesting HD and homozygotes a 74% chance of manifesting HD. Further research also identified a deletion of the pericentromeric region of chromosome 10 in total aganglionosis, and from this genetic study mutations in the ret oncogene were identified, this oncogene surprisingly produced HD rather than the medullary cell carcinomas initially identified with this gene.5 The consanguinity as expressed by the proportion of first and second cousin marriages compared with the background population is considerably increased. Thus, the main reason for the increase in HD in Oman is likely to be because of the increasing prevalance of recessive mutations. Some of these may be of low penetrance and therefore formal segregation analysis does not confirm the classical segregation ratio of autosomal recessive inheritance. If there are further recessive mutations to be identified it is likely the detailed study of isolated inbred populations such as this will be fruitful.
REFERENCES 1. Badner JA, Sieber WK. Garver KL. et al: A Genetic study of Hirschprung disease. Am J Hum Genet 46:568-580. 1990 2. Bodtan M, Carter CO: A family study of Hirschsprung’s disease. J Med Genet 26:261-277,1963 3. Passarge E: The genetics of Hirschsprung’s disease: Evidence for heterogeneous etiology and a study of sixty three families. N Engl J Med 276:138-143, 1967 4. Spouge D, Baird PA: Hirschsprungs disease in a large birth cohort. Teratology 32:171-177. 1985 5. Lyonnet S, Bolmo A. Pelet A, et al: A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nature Genet 4:346-348, 1994 6. Puffenberger EG, Hosoda K, Washington SS, et al: A mtssense mutatton of the endothelin-B receptor gene in multtgemc Hirschsprung’s disease. Cell 79: 1257-1266, 1994 7. Winter RM, Baraitser M: Multiple Congenital Anomalies: Adiagnostic Compendium. London, Chapman and Hall, 1991, pp 384-385 8. Larson LT, Okmian L, Kristafferson UN: No correlation between hypertermia during pregnancy and Hirschprung’s disease in the offspring. (Letter) Am J Med Genet 32:260-261. 1989 9. Haldane JBS, Smith CAB: A simple exact test for birth order effect. Ann Eugen 14: 117- 124.1947 10. Emery AEH: Methodology in Medical Genetics. An Introduction to Statistical Methods. Edinburgh, Churchill Livingstone, 1976, pp 108-111
11. Goldberg EL: An epidemiological study of Hirschsprung’s disease. Int J Epidemiol 13:479-485. 1984 12. Russell MB. Russell CA, Niebuhr E: An epidemiological study of Hirschsprung’s disease and additional anomalies. Acta Paed 83.6871,1994 13. Ikeda K, Goto S: Diagnosis and treatment of Hirschpnmg’s disease in Japan, Ann Surg 4:400-405. 1994 14. Al-Amri SM; Makajoula D, Al-Rasheed RS, et al: Hirschprung’s disease m adult. Saudi Med J 17.82-85. 1996 15. SmithMSR. Edwards MJ, Upfold JB: The effect of hyperthermia on the fetus. Dev Med Child Neurol28:803-813, 1986 16. Shah KN, Dalal SJ. Desai MP, et al: White forelock, pigmentary disorders of the irides and long segment Hirschsprung disease: Possible variant of Waardenburg disease. J Pediatr 99:432-435. 198 1 17. Attie T, Till M, Amiel J. et al: Endothelin B receptor gene mutation in a consangineous family with Waardenberg-Hirschsprung Disease: A possible variant of Waardenberg disease. J Pediatr 99:432435. 1981 18. Lamont MA. Fitchett M. Dennis NR: Interstitial deletion of distal 13q associated with Hirschsprung’s disease. J Med Genet 26: 100-104, 1979 19. Bottam A, Xie Y, Binkert F, et al: A case of Hirschprung disease with a chromosome 13 microdeletion, de1(13)cq32.3q33.2): Potential mapping of one disease locus. Hum Genet 87:748-750. 1991