Hirschsprung's disease in a kindred: A possible clue to the genetics of the disease*

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A nine generation kindred, the first generation dating back to the early 18th century, existing in the Mennonite population of central Pennsylvania is described in terms of the incidence of documented and presumptive Hirschsprung's disease. This kindred was developed by tracing back family lines, by the use of the “circle letter” and three family history books, and by personal interviews with key family members. In the ninth (current) generation, involving at least 5 families, 8 out of 14 children (57%) have documented evidence of Hirschsprung's disease; 4 out of 14 had congenital deafness (29%); 2 had Waardenburg's syndrome (14%); and 1 had Down's syndrome (7%). Only 1 out of the 14 had total colonic involvement. Investigation of the sixth-ninth (last 4) generations shows 22 out of 100 (22%) to have definite or strongly presumptive evidence of Hirschsprung's disease. The opportunity to study this unique kindred, which can be traced back to a single source, exhibiting a very high incidence of Hirschsprung's disease with an unusually high incidence of associated congenital anomalies and without significant association of total colonic disease has provided us with a better understanding of the genetics underlying this disease.

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    A number of developmental conditions have been associated with TCA,51 along with several known syndromes inherited in an autosomal-dominant manner. Although the pattern of conditions associated with HSCR has already been of great value in revealing many of the genetic natures and associations of the disease,54,55 there appears to be no consistent association with specific anomalies and TCA. Associations with chromosomal abnormalities (including Down syndrome)56,57 and other syndromes such as the congenital hypoventilation syndrome (with a paired-like homeobox 2b [PHOX2] gene mutation57) as well as associations with other congenital anomalies (eg, ileal atresia58,59) and tumors of neural origin60 indicate a probable genetic mechanism.

  • A review of genetic mutation in familial Hirschsprung's disease in South Africa: towards genetic counseling

    2008, Journal of Pediatric Surgery
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    The risk of an inherited familial predisposition is well established (2.4%-9%) [3,4], as well as occurrence in mono- and dizygotic twins [12,10] and a 12% association with chromosomal anomalies. Nevertheless, no clear pattern of inheritance exists [3,15], and autosomal dominant [16,17], recessive [18-20], and multigenic patterns [21] have all been reported. Most HSCR cases can thus be classified as complex genetic disorders where familial aggregation is observed without consistent mendelian inheritance [22].

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*

Presented before the 30th Annual Meeting of the Surgical Section of the American Academy of Pediatrics, New Orleans, La., October 31–November 1, 1981.

1

From the Division of Pediatric Surgery, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Penn.

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