Immune deficiency in familial duodenal atresia

Immune Deficiency in Familial Duodenal Atresia By SW.

Moore,

G. de Jongh, P. Bouic, R.A. Brown, Cape Town, South Africa

0 The familial occurrence of duodenal atresia is uncommon. This study evaluated the inheritance patterns, the nature and associations, and the presence of immunologic deficits in duodenal atresia recurring in at least three siblings each in two nonrelated families. In the first family, an association with Fanconi’s anemia was observed in three of seven pregnancies (2 boys, 1 girl) suggesting an autosomal recessive mode of transmission. Patients died as a result of overwhelming (fungal) septicemia in association with pancytopenia. In a second family, identical multiple atresias occurred in two female siblings born 18 months apart and a third child with a duodenal stenosis. Overwhelming sepsis and a T-cell dysfunction was seen in the postoperative period, which had partially corrected by follow-up at 5 months. A history of family occurrence of duodenal atresia should alert the physician to the possibility of associated pathology including immune deficiency states. Copyright o 1996 by W.B. Saunders Company

and G. Kirsten

multiple congenital abnormalities, winch included microcephaly, micrognathia, low set abnormal ears. syndactyly, clinodactyly and single palmar creases. G-banded chromosome analysis showed 46,XY, de1 (7)(qllq22). The third pregnancy resulted in a spontaneous abortion caused by a trisomy of chromosome 10. Duodenal atresia and Fanconi anemia were once more diagnosed in the fourth son (FlV4) who had an absent 4th thumb and malrotation of the gut in addition to the duodenal atresia. Subsequent death from septicaemia occurred. The only living son (FlV5) was examined at 9 years of age. and no stigmata of Fanconi anemia were detected. A further pregnancy (FlV6) was terminated for trisomy 21. The subsequent pregnancy was the female fetus with Fanconi anemia and duodenal as well as esophageal atresia. Although consanguinity was denied, the maternal grandmother had the same surname as the father. Chromosome studies (GBanding and Fanconi anemia complementation group C (FACC)) were normal. Case 2

INDEX WORDS: Familial duodenal coni anemia, immunodeficiency.

atresia,

inheritance,

Fan-

D

UODENAL ATRESIA is a well-known cause of gastrointestinal obstruction in the neonate; its estimated prevalence is 1 in 10,000 to 14,000 live births.’ Current understanding of the etiology of duodenal atresia is based on the Tandler theory of failure of recanalization of the solid embryonic duodenum during the 8th to 10th week of intrauterine development.2 More than 80% of duodenal atresias occur in the region of the ampulla of Vater. The aim of this study was to evaluate the inheritance patterns, the nature of the duodenal atresia, and the role of immunologic problems in two families with duodenal atresia occurring in three siblings. CASE

REPORTS

Case 1 A 40-year-old mother (gravida 7, para 4) from an isolated rural area was referred with an antenatal ultrasonographic diagnosis of a fetal duodenal atresia. A repeat ultrasound examination at 23 weeks showed the fetus having severe hydrocephalus as well as other abnormalities, and termination of pregnancy was performed. The 330-g female fetus (FlV.7) was noted to have an absent left thumb, a hypoplastic right thumb, a single umbilical artery, a horseshoe kidney, a Dandy Walker ventricular cyst, and an esophageal as well as a postampullary duodenal atresia. associated with Fanconi anemia. A family case study (Fig 1) showed that two previous male siblings had had duodenal atresia associated with clinical features of Fanconi anemia. The firstborn boy (FIV.l) was noted to have fingerized thumbs and associated duodenal atresia, which were repaired successfully in the neonatal period. He subsequently died, as a result of fungal septicemia associated with pancytopenia, at 16 years of age. The second child (FlV.2) was hypotonic and had JournalofPediatric

Surgery,

Vol 31, No 12 (December),

1996: pp 1733.1735

In an additional nonrelated family, identical multiple atresias occurred in two female siblings born 18 months apart. The first sibling underwent successful surgical management at another institution but died of overwhelming sepsis in the postoperative period. An immunologic deficiency was suspected but not proven. The second female child (patient VT) was referred to our institution with an antenatal diagnosis of duodenal atresia on antenatal sonographic examination. Her birth weight was 2,500 g, and gestational age was 38 weeks with scoring. On examination, she drained bile freely from the nasogastric tube and an abdominal x-ray showed a classical double bubble appearance. Chromosome studies showed a normal female configuration (46Xx) and no consanguinity was present. HIV testing was negative. At surgery, multiple postampullary duodenal atresias were identified in the 3rd and the 4th part of the duodenum, anatomically identical to the previous findings in her sibling. Surgical correction of the duodenal atresia resulted in survival but the patient developed multiple bacterial infections in the neonatal period. On further investigation these infections were shown to result from an immunologic qualitative and quantitative T-cell dysfunction. The baselme mitogenie responses of the patient’s lymphocytes showed severely depressed Phytohemagglutinin, Concanavalin A, Protein A, and Candida antigen responses relative to healthy controls (less than 20% of control responses for all mitogens). On follow-up 5 months later. the T-cell responses had greatly improved whereas the B-cell responses still showed abnormalities. The improved T-cell responses were probably caused by a normalization of the T-cell phenotypes in the peripheral blood; suggesting a partial thymic hypoplasia (DiGeorge syndrome). The serum gammaglobulin level

From the Depatiments of Paediatric Surgery. Human Genetics, Immunology, and Neonatology. Tygerberg Hospital, and the Depaltment of Paediatn’c Surgery, Red Cross Chddrenk Hospital, Cape Town, South Africa. Address reprint requests to Professor S. W. Moore, Department of Paedzatnc Surgery, Uruverszty of Stellenbosch, Faculty of Medlcme. Tygerberg 7505, South Africa. Copyright o 1996 by W.B. Saunders Company 0022-346819613112-0036$03.00/O 1733

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II

Ill

IV 123

me

4

567

Duodenal atresia plus Fanconi Anaemia

Fig 1. Genetic pedigree of family in case 1. Chart indicates the association between duodenal atresia and Fanconi anemia. Patients are identified by F (Fanconi anemia), the generation (eg, IV), and the order of birth (eg, 1.2, etc).

remained low, possibly because of the abnormally low B-cell functions as indicated by the Protein A responses. She remains clinically well but a third child born recently to this family underwent surgery at another institution for duodenal stenosis. DISCUSSION

The first report of a familial occurrence of duodenal atresia is attributed to Pequet et al.3 Boyden et al4 suggested a genetically transmissable factor, but although duodenal atresia may occur as one of a number of anomalies in Down’s syndrome, familial recurrence is uncommon .5-8Reports of familial occurrence of duodenal atresia include offspring of consanguinous marriages or patients with mucoviscidosis.lsg In a review by the surgical section of the American Academy of Pediatrics, Fonkalsrud et aI6 reported only 13 instances of familial recurrence of duodenal atresia out of 503 patients with congenital duodenal obstruction giving a prevalence of 2.6%. Fonkalsrud’s series included four siblings with duodenal atresia in one family. Further reportsr,5bJOJt have confirmed the low incidence of familial duodenal atresia, and the majority appear to be in female offspring of consanguinous marriages.l At least one case of an affected father and son has been reported.lO Although familial duodenal atresia is probably not related to other rare autosomal recessive multiple gastrointestinal atresia syndromes associated with prepyloric webs and jejunoileal (type 3b) apple peel atresias,aJ*-ls certain similarities are evident. The genetic basis of familial duodenal atresia is still unknown. Trisomy 21 is a commonly associated6 genetic defect but the significance of the identified chromosomal abnormalities (ie, 46,XY, de1 (7)(qllq22), trisomy 10 and 21) in siblings of case 1 remains difficult to

ET AL

evaluate. Other reported genetic connections associated with duodenal atresia include a ring on chromosome 4.16 The mode of inheritance is not yet clear. The association between duodenal atresia and Fanconi anemia in three children in case 1 lends support to an autosomal recessive inheritance pattern. The opposite is true of case 2 where the mode of inheritance appears to be dominant. Best1 reviewed all cases reported up to 1989 and showed, by means of segregation analysis, that a multifactorial determination or a dominant gene with reduced penetration could not be excluded. In addition, there is considerable overlap in the abnormalities associated with Fanconi anemia, the VACTERL association,17J8 and radial ray defectsI which may help to explain some of the associated abnormalities. Fanconi anemia is a rare autosomally recessive disorder characterized by chromosomal instability, congenital anomalies, cell cycle anomalies, and cancer predisposition. It is thus associated with a wide spectrum of associated congenital abnormalities. The link between Fanconi anemia and duodenal atresia probably originates in disturbances within the cell cycle that occur in Fanconi’s anemia, which may subsequently result in failure of vacuolation within the solid core of developing intestinal cells. This concept therefore lends support to the Tandler theory of pathogenesis. 2 The recent mapping of Fanconi anemia complementation group C and xeroderma pigmentosum to the 9q22-31 regionzO suggests an avenue for further research. The link with immune deficiency is less clear. In case 1 septicemia was the ultimate cause of death in two sibling boys with duodenal atresia and Fanconi anemia. The quantitative and qualitative T-cell dysfunction detected in case 2, suggested a partial Di George syndrome. The successful outcome in patients in whom this was recognized suggests that termination of pregnancy is not justified in patients with a familial recurrence of duodenal atresia. The familial recurrence of multiple duodenal atresias in two children is extremely uncommonZ1 but has previously been reported in the first part of the duodenum by Mishalany and Der Kaloustian.’ More than one etiologic mechanism has been suggested.13a2* Multiple areas of intestinal atresia have, however, been previously reported in association with a severe combined immunodeficiency syndrome in three siblings.23 A further report describes a patient with immunodeficiency and graft versus host disease,24 and

IMMUNE

DEFICIENCY

IN FAMILIAL

DUODENAL

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ATRESIA

immunodeficiency has also been reported in association with structural gastrointestinal defects but has been attributed to excessive losses and maInutritionz4

A history of family occurrence of duodenal atresia should alert the physician to the possibility of associated pathology including immune deficiency states.

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J: Zur Entwicklungsgeschichte des menschlichen Duodenums in fruhen Embryonalstadien. Morph Jahrb 29:187216,1900 3. Pecquet

AR, Watson EH: Duodenal atresia occurring in siblings. Univ Mich Med Bull 25:363-370, 1959 4. Boyden EA, Cope JG, Bill AH: Anatomy and embryology of congenital intrinsic obstruction of the duodenum. Am J Surg 114:190-202,1967 5. Hyde JS: Congenital duodenal atresia in four sibs. JAMA 191:146-147,1965 6. Fonkulsrud EW, deLorimier AA, Hays DM: Congenital atresia and stenosis of the duodenum. Pediatr 43:79-83, 1969 7. Mishalany HG, Der Kaloustian VM: Familial multiple-level intestinal atresia: A report of 2 siblings. J Pediatr 79:124-125, 1971 8. Berant M, Kahama D: Familial duodenal atresia. Arch Dis Child 45:281-282, 1970 9. Blank CE, Okmian L, Robbe H: Mucoviscidosis and intestinal atresia. A study of 4 cases in the same family. Acta Pediatr Stand 54:557-565.1965

10. Mitchell CE. Marshall DC, Reid WD: Preampullary congenital duodenal obstruction in a father and son. J Pediatr Surg 28:1582-1583,1993

11. Gahukamble DB, Khamage AS, Shaheen AQ: Duodenal atresia: Its occurrence in siblings. J Pediatr Surg 29:1599-1600, 1994 12. Martin CE, Leonidas JC, Amoury RA: Multiple gastrointestinal atresias with intraluminal calcifications and cystic dilatation of bile ducts: A newly recognised entity resembling “a string of pearls.” Pediatrics 57:268-271, 1976 13. Rickham PP, Karplus M: Familial hereditary intestinal atresia. Pediatrics 73:753-755,197l

14. Arnal-Monreal F, Pombo F, Capdevila-Puerta A: Multiple hereditary gastrointestinal atresias: Study of a family. Acta Pediatr Stand 72:773-777,1983 15. Farag TI, Al-Alwadi SA, El-Badramany MH, et al: Second family with “apple peel” syndrome affecting four siblings: Autosoma1 recessive inheritance confirmed. Am J Med Genet 47:119-121, 1993 16. Halal F, Vekemans M: Ring chromosome 4 in a child with duodenal atresia. Am J Med Genet 37:79-82, 1990 17. Porteous MEM, Cross I, Burn J: VACTERL with hydrocephalus: One end of the Fanconi anaemia spectrum of anomalies. Am J Hum Genet 43:1032-1034,1992 18. Wang H, Hunter AGW, Clifford B, et al: VACTERL with Hydrocephalus: Spontaneous chromosome breakage and rearrangement in a family showing apparent sex-linked recessive inheritance. Am J Hum Genet 47:114-117,1993 19. Cox H, Viljoen D, Versveld G, et al: Radial ray defects and associated anomalies. Clin Genet 35:322-330,1989 20. Strathdee CA, Gavish H, Shannon WR, et al: Cloning of cDNAs for Fanconi’s anaemia by functional complementation. Nature 356:763-767, 1992 21. Stringer MD, Brereton RJ, Drake DP. et al: Double duodenal atresiaistenosis: A report of four cases. J Pediatr Surg 27:576-580,1992 22. Samuel

M, Sajwany MJ, Vaishnav A: Multiple gastrointestinal atresias. Pediatr Surg Int 9:587-589, 1994 23. Moreno LA, Gottrand F, Turck D, Manouvrier-Hanu S, et al: Severe combined immunodeficiency syndrome associated with autosomal recessive familial multiple gastrointestinal atresias: Study of a family. Am J Med Genet 37:143-146,199O 24. Walker MW, Love11 MA, Kelly TE, et al: Multiple areas of intestinal atresia associated with immunodeficiency and posttransfusion graft versus host disease. J Pediatr 123:93-95, 1993