Familial jejunal atresia with renal dysplasia

Familial Jejunal Atresia With Renal Dysplasia By

Ramzi A. Kilani,

Paul Hmiel, Michael

K. Garver, Sadeesh K. Srinathan, St Louis, Missouri

0 Although jejunal atresia occasionally may occur with a familial pattern, an association with renal disease has not been described. The authors report on three family members treated over two generations, all of whom had both proximal jejunal atresia and renal dysplasia. This association was most likely inherited as an autosomal dominant trait. Copyright o 7996 by W.B. Saunders Company INDEX WORDS: diseases.

Jejunal

atresia,

renal

dysplasia,

inherited

J

EJUNOILEAL ATRESIA is the most common cause of bowel obstruction in the newborn.’ Martin and Zerella classified jejunoileal atresia into five types according to anatomic appearance: type I (mucosal web), type II (ends separated by a fibrous cord), type IIIa (ends separated by a V-shaped mesenteric defect), type IIIb (“apple peel” deformity), and type IV (multiple atresias).2 Type IIIb most commonly occurs with a familial pattern of inheritance, aIthough types I, II, and IV also have occurred in families.3 Congenital anomalies of the urinary tract occur in up to 10% of the population,4 with renal dysplasia and agenesis accounting for a small proportion. Although renal dysplasia and agenesis have occurred in association with gastrointestional tract malformations, these cases represented sporadic syndromes or chromosomal anomalies. Isolated renal dysplasia or agenesis within a kindred has been termed hereditary renal adysplasia. We report on a family in which three members in two generations had both jejunal atresia and renal dysplasia. These cases represent the first report of this association, as well as a rare example of familial jejunal atresia that is not type IIIb. CASE REPORTS

Patient 1 (Mother) A white girl was born at 34 weeks’ gestation. She was found to have type II jejunal atresia at the ligament of Treitz, which was repaired on the second day of life. An elevated serum creatinine level was noted postoperatively, which persisted throughout infancy. An intravenous pyelogram demonstrated no left kidney and a poorly functioning, presumably dysplastic right kidney. At age 21 she became pregnant, and intrapartum renal insufficiency developed, with a creatinine clearance of 46 mL/min/l.73 m2 (normal, 120 to 150 mLiminil.73 m2), as well as gestational diabetes and thrombocytopenia. Prenatal ultrasonography showed dichorionic twins. Repeat scans at 29 weeks’ gestation showed dilated proximal loops of small bowel, with hyperperistalsis in both fetuses. The amniotic fluid volume was normal in twin A and was elevated in twin B. At 31 weeks’ gestation, diffuse echogenecity in JournalofPediatric

Surgery,

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No lO(October),1996:

pp 1427-1429

Karen M. Wickline,

and Jacob

C. Langer

both kidneys was noted in both twins. Amniocentesis was not performed. The infants were delivered at 33 weeks’ gestation by vaginal delivery after onset of labor.

Patient 2 (Twin A) This male infant had proximal jejunal atresia documented by plain radiographs and an upper gastrointestinal barium study. Laparotomy showed type I atresia, characterized by a dilated jejunum proximal to two webs, 3 and 4 cm beyond the ligament of Treitz. Web incision and transverse jejunoplasty were performed. The histopathological features of the web are shown in Fig 1. Renal ultrasonography showed echogenic renal cortices and preserved corticomedullary distinction, without renal cysts. Subsequent duodenal hypomotility necessitated a second laparotomy for tapering of the dilated proximal duodenum, and a renal biopsy was performed. The renal biopsy histopathology is shown in Fig 2. The initial creatinine level was 2.2, which decreased to 1.0 by the time of discharge. The child is now 1 year old and thriving, although his serum creatinine level remains moderately elevated (1.0).

Patient 3 (Twin B) This female infant had jejunal atresia diagnosed through plain radiography. Laparotomy showed type I atresia, with a single jejunal web 10 cm distal to the ligament of Treitz. Web incision and tapering jejunoplasty were performed. An elevated serum creatinine level (2.1) prompted a renal sonogram, which demonstrated echogenic renal cortices, preserved corticomedullary distinction, and bilateral renal cortical cysts. The child is thriving at 1 year of age; her serum creatinine level is 0.9. A summary of the bowel and renal findings for the three cases is shown in Fig 3. DISCUSSION

Intestinal atresia is believed to result from either an intrauterine ischemic event6 or faiIed recanahzation of the solid epithelial plug stage between the 5th and 11th weeks of life.7 The latter theory has been favored for duodenal atresia and for type I and some type II jejunoileal lesions, because epithelial proliferation occurs in all portions of the intestine, including the jejunum,8 and failure of recanalization appears to be a more likely explanation. Rittenhouse reported that the septa in type I atresias were covered with epithelium on both surfaces, with an intact muscularis mucosa.9 The presence of numerous epithelial retention cysts in the atretic septa and the intact muscular

From the Departments of Pediatrics and Surgery Washington University School of Medicine, St Louis, MO. Address reprint requests to Jacob C. Langeu, MD, Division of Pediattic Swgey, Rm 5WI2, St Louis ChildrenS Hospital, One Children’s Place, St Louis, MO 63110. Copyright o I996 by W B. Saunders Company 0022.3468196/3110-0024$03.0010 1427

1428

KILANI

ET AL

Ffg 1. Photomicrographs of transverse sections through the jejunal web from case 2, stained with fi&E. (A) Low-power (x25) magnification shows bridging of the lumen by the epithelialized septum. (B) High-power [200x) view of the septum shows epitheliul structures.

layers suggested failure of recanalization during embryological development. However, this theory did not explain the presence of an intact muscularis mucosa in the atretic septa. Louw and Barnard suggested that the atretic septum in type I atresia is the result of circumferential fusion of necrotic mucosa following ischemia in a short segment of intestine.‘j In addition, types I, II, and IIIa atresia have been produced in fetal animals by interrupting the blood supply to the intestine in utero.6J0J1 Recent work by Puri et al, who used microscopic analysis of clinical material from 59 neonates with jejunoileal atresia, suggested that all familial cases of atresia, and some nonfamilial ones, result from a malformation of the intestine rather than from an intrauterine ischemic insult.12

MOTHER

IOcm

Fig 2. Renal biopsy specimen from case 2 showed normalappearing glomeruli (small arrows), normal tubules (arrowheads), and cartilaginous structure characteristic of renal dysplasia (large arrows). (H&E, original magnification x200).

Fig 3. Summary of the intestinal patients. LT. ligament of Treitz.

and renal

findings

of the

three

FAMILIAL

JEJUNAL

1429

ATRESIA

Approximately one dozen reports of familial jejunal atresia have appeared in the literature. The most common forms to present in families have been type IIIb (apple peel)13 and type IV (multiple atresias).14 An autosomal recessive mode of inheritance has been suggested for both of these. A few reports of isolated jejunal atresia in families exist,15 but a mode of inheritance has been difficult to determine. Many congenital anomalies have been associated with intestinal atresia. Most of these anomalies involve the gastrointestinal tract,r and hereditary association of jejunal atresia with renal dysplasia has not been reported previously. Most cases of renal dysplasia are sporadic, although familial occurrence as hereditary renal adysplasia has been established in some kindreds. In these cases, the findings have represented a spectrum of disease, from total bilateral renal agenesis to unilateral dysplasia and asympto‘. matic anomalies. Different anomalies may be observed in members of the same family, which suggests variable expression of the disease. Despite limited kindred data, autosomal dominant,16 autosomal recessive,17 and X-linked’s modes of inheritance have been implicated. All three cases described herein involved the proximal jejunum, but the mother had type II atresia and both children had type I atresia, one of which

involved multiple webs within 2 cm of each other. This family supports the theory that type I and II atresias may be caused by a common mechanism, most likely developmental rather than ischemic in nature. The findings of renal adysplasia and jejunal atresia in three members of a family over two generations, in the absence of other features of malformation syndromes, are most consistent with autosomal dominant inheritance, and may reflect a single gene syndrome. How can we link defects in organogenesis of both the intestine and the kidney in this family? Development of these epithelial organs depends on complex interactions of progenitor cells, extracellular matrix, and the local and systemic production of polypeptide growth factors. i9 Manipulation of any of these components has resulted in abnormal development in various experimental models. A recent example involving both the renal and the intestinal systems is the Ret proto-oncogene, which has been shown to be abnormally expressed in some cases of Hirschsprung’s disease.20 Transgenic mice, which lack the Ret tyrosine kinase receptor, exhibit abnormal development of both the gut and the urinary tract, and die of renal failure shortly after birth. 21 Further investigation of this and other families, using Ret and similar genes, may shed light on this question.

REFERENCES 1. Lister J: Intestinal atresia and stenosis, excluding the duodenum, in Lister J, Irving IM (eds): Neonatal Surgery. London, England, Buttenvorths, 1990, pp 453-473 2. Martin LW, Zerella JT: Jejunoileal atresia: A proposed classification. J Pediatr Surg 11:399-403, 1976 3. Touloukian RJ: Intestinal atresia and stenosis, in Holder TM, Ashcraft KW (eds): Pediatric Surgery. Philadelphia, PA, Saunders, 1993, pp 305-319 4. Bernstein J: Rena1 hypoplasia and dysplasia, in Edelman CJJ (ed): Pediatric Kidney Disease. Boston, MA, Little, Brown, 1992, pp 1121-1137 5. Buchta RM, Visekul C, Gilbert EF, et al: Familial bilateral renal agenesis and hereditary renal adysplasia. Z Kinderheilk 115:111-129,1973 6. Louw JH, Barnard CN: Congenital intestinal atresia, observations of its origin. Lancet 2:1065,1955 7. Guttman FM: The pathogenesis of intestinal atresia. Surg Gynecol Obstet 141:203-206,1975 8. Lynn HB, Espinas EE: Intestinal atresia. Arch Surg 79:357361,1959 9. Rittenhouse EA: Multiple septa of the small bowel: Description of an unusual case, with review of the literature and consideration of etiology. Surgery 71:371-379, 1972 10. Abrams JS: Experimental intestinal atresia. Surgery 64:185191,1968 11. Tepas JJ, Wyllie RG, Shermeta DW, et al: Comparison of

histochemical studies of intestinal atresia in the human newborn and fetal lamb. J Pediatr Surg 14:376-380,1979 12. Puri P, Fujimoto T: New observations on the pathogenesis of multiple intestinal atresias. J Pediatr Surg 23:221-225, 1988 13. Blyth H, Dickson JAS: Apple peel syndrome. J Med Genet 6:275-277,1969 14. Guttman FM, Braun P, Garance PH, et al: Multiple atresias and a new syndrome of hereditary multiple atresias involving the gastro-intestinal tract from stomach to rectum. J Pediatr Surg 8:633-640,1973 15. Rickham PP, Karplus M: Familial and hereditary intestinal atresia. Helv Paediatr Acta 26:561-564, 1971 16. Murugasu B, Cole BR, Hawkins EP, et al: Familial renal adysplasia. Am J Kidney Dis 18:490-494,199l 17. McPherson E, Carey J, Kramer A, et al: Dominantly inherited renal adysplasia. Am J Med Genet 26:863-872,1987 18. Cain DR, Griggs D, Lackey DA, et al: Familial renal agenesis and total dysplasia. Am J Dis Child 128:377-380,1974 19. Kreidberg JA, Sariola H, Loring JM, et al: WT-1 is required for early kidney development. Cell 74:679-691,1993 20. Romeo G, Ronchetto P, Luo Y, et al: Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschprung’s disease. Nature 367:377-378, 1994 21. Schuchardt A, D’Agati V, Larsson-Lomberg L, et al: Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367:380-383,1994