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Journal of Pediatric Gastroenterology & Nutrition:
Original Articles

Syndrome of Intractable Diarrhoea with Persistent Villous Atrophy in Early Childhood: A Clinicopathological Survey of 47 Cases

Goulet, O. J.; Brousse, N.*; Canioni, D.*; Walker-Smith, J. A.†; Schmitz, J.; Phillips, A. D.†

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Author Information

Departments of Pediatrics and *Histopathology, Hôpital des Enfants Malades, Paris, France; and †University Department of Paediatric Gastroenterology, Royal Free Hospital, London, United Kingdom

Received May 27, 1997; revised August 7, 1997; accepted August 20, 1997.

Address correspondence and reprint requests to Dr. A. Phillips, University Department of Paediatric Gastroenterology, Third Floor, Royal Free Hospital, Pond Street, London NW3 2QG, U.K.

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Abstract

Background: The syndrome of intractable diarrhoea of infancy is heterogeneous and includes several diseases with diverse aetiologies. This study determines whether diagnostic categories can be defined on the basis of clinicopathological analysis.

Methods: European Society of Paediatric Gastroenterology, Hepatology and Nutrition members were surveyed to identify cases of intractable diarrhoea with persisting small intestinal enteropathy. A retrospective clinicopathological analysis was performed on cases showing life-threatening diarrhoea within the first 24 mo of life and requiring total parenteral nutrition, which were characterized by persistent villous atrophy, and resistance to therapy.

Results: Forty-seven infants were identified with intractable diarrhoea. Villous atrophy was of varying degrees with (group I, n = 24) or without(group II, n = 18) lamina propria mononuclear cell infiltration. Group I presented later, had gut auto-antibodies, and a higher prevalence of protein-losing enteropathy; a subset (group Ia, n = 12) also had extraintestinal symptoms of autoimmunity associated with a later onset of larger volume diarrhoea. Group II presented early; 8 cases (group IIa) had phenotypic abnormalities and a low birth weight; the remaining 10 (group IIb) showed mild-to-moderate villous atrophy, epithelial tufting, and abnormal crypts. Group III included five patients in whom no specific features were recognised. Twenty-one (45%) died at a median age of 24 months, 20 (43%) remained dependent on parenteral (n = 16) or enteral tube(n = 4) feeding, 4 (9%) received elimination diets plus other therapies, and 2 (4%) were lost to follow-up.

Conclusions: Clinicopathological analysis allowed distinct disease groups to be identified, allowing a provisional classification to be made. This straightforward approach forms a basis for future research in this exceptionally difficult paediatric condition.

The syndrome of intractable diarrhoea of infancy remains a difficult challenge for the paediatrician. It was first described by Avery et al. in 1968 (1) with the following features: diarrhoea of more than 2 weeks' duration, age less than 3 months, and three or more negative stool cultures for bacterial pathogens (1). All cases were managed with intravenous fluids and despite hospital management, diarrhoea was persistent and intractable with a high mortality rate. The definition, presentation, and outcome of intractable diarrhoea have changed considerably during the last 2 decades because of a better understanding of the pathology of the small bowel mucosa and to major improvements in nutritional management. The term “intractable diarrhoea in infancy” embraces a heterogeneous syndrome with a diverse aetiology. By “intractable diarrhoea with persistent villous atrophy in early childhood,” we allude to children whose diarrhoea starts within the first 2 years of life, rapidly becomes life-threatening, and leads to dependence on total parenteral nutrition (TPN). It is associated with a persistent histological intestinal lesion, is due neither to a specific immune deficiency nor a sensitisation to a common food protein (e.g., cow's milk and gluten), and may continue for years despite various therapeutic trials.

Progress has been made within this heterogeneous group of patients in the characterisation of different conditions such as autoimmune enteropathy(2-20) and microvillous atrophy (21-23). An attempt to classify intractable diarrhoea according to villous atrophy was proposed on the basis of immunohistological criteria emphasising the role of activated T cells in some enteropathies (24). The aim of this survey was to broaden the scope of such a classification and to ascertain the clinical presentation, the main histological, biological, and immunological features, and the outcome of this rare condition in which pathophysiology remains elusive. It was hoped that gathering cases together would allow correlations and analogies to emerge and a clinicopathological classification could be proposed. Microvillous atrophy was excluded from this survey because it has been considered in detail previously (23).

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PATIENTS AND METHODS

Population

A survey to identify patients with intractable diarrhoea was made during the first 3 months of 1992 among members of the European Society of Paediatric Gastroenterology and Nutrition. Returned questionnaires were used to form a data base, and histological material was requested from those cases that satisfied the entry criteria. The three main diagnostic criteria were:

* Severe life-threatening diarrhoea occurring within the first 24 months of life that required TPN

* Persistent villous atrophy demonstrated in consecutive biopsies

* Resistance to treatment despite several therapeutic trials.

Initially, more than 90 cases were submitted from nine countries. Twenty-five cases were excluded either because they involved only protracted diarrhoea, or they did not fulfil the inclusion criteria (i.e., the patients were older than 24 months at onset of diarrhoea, or the enteropathy resolved), or they were cases of severe colitis (25). In 66 cases, the diagnosis of intractable diarrhoea with persisting villous atrophy was established, but the present study concerns only the 47 cases in which the diagnosis was confirmed by a review of histological material.

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Data Base

The questionnaire for each case included family history, pregnancy and birth events, clinical and biological data, treatment, and outcome. This formed a data base, which was analysed according to histological findings, discussed next.

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Histological Study

The age at the time of biopsy was recorded. Sections stained with haematoxylin and eosin were studied using routine light microscopy. Biopsy analysis was performed separately in Paris and London, and results were then compared and the patients were classified.

Histological analysis (Table 1) included the degree of villous atrophy (mild, moderate, severe); crypt size and appearance[hyperplastic or normoplastic (no case of hypoplasia was identified)], necrotic or branched, and the presence of crypt abscesses; epithelial cell height and appearance (an epithelial cell tuft was defined as a focal crowding and disorganisation of surface enterocytes); the mononuclear cellularity of the lamina propria; the density of intraepithelial lymphocytes; an increased number of neutrophils and eosinophils either in the epithelium or in the lamina propria; and the uniform or patchy nature of the enteropathy. The fulfilment of at least five of these seven criteria led to an inclusion into group I or II.

Table 1
Table 1
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Statistical Analysis

Data were recorded and analysed on a personal computer with validated software. Results were expressed as means and standard deviations, medians with ranges, or percentages. Clinical data were analysed using the Mann-Whitney test for nonparametric values and the Chi square test for percentages. A p value of 0.05 or less was taken as significant.

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RESULTS

The main clinical data concerning the patients are summarised inTables 2 and 3. Children were born between the years 1974 and 1991. Clinical and/or biological data from several cases have been reported in article or abstract form (see references in the Tables). There were 20 (43%) girls and 27 boys (57%) from 47 families. Parents were of white(81%), Arab (17%), or Asian (2%) origins. Five patients had consanguineous parents (first-degree in three cases). Information concerning siblings was provided in 47 families; in three families, two to four siblings had died of intractable diarrhoea in the first months of life, and in six families, one sibling had died of intractable diarrhoea. Therefore, evidence of a familial condition was present in 9 of 47 (19%) families.

Table 2
Table 2
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Table 3
Table 3
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Pregnancy was uneventful, except in four cases of threatened abortion in the third month, gravida toxaemia, and two urinary tract infections during the last trimester, respectively. Gestation varied from 32 to 41 weeks (median = 40 weeks); 11 (23%) were preterm (32-37 weeks), and 23 (49%) were term (40-41 weeks). No case had hydramnios. Birth weights ranged from 1,180 to 4,450 g(median = 2,965 g) and did not correlate with gestation. Twelve (25%) were small for gestational age, with birth weights varying from 1,180 to 2,020 g for a gestation between 35 and 41 weeks. Twenty-nine (62%) were breast fed at birth; the other 18 (38%) were bottle fed with a standard infant formula.

Diarrhoea started between 1 day and 24 months after birth (median = 42 days); 9 cases (19%) during the first week, 12 children (26%) between the eighth day and the end of the first month, and 14 patients (30%) during the second and third months of life (Fig. 1). At the onset of diarrhoea, 13 children (28%) were breast fed, 27 (57%) received a standard infant formula, and 7 (15%) had normal oral feeds for their age. Diarrhoea was watery, abundant (123 ± 86 ml/kg/day, median 100 ml/kg/day) when the infant was fed, and persisted when on nil by mouth (50-150 ml/kg/day). In 10 cases (21%), the stools were also noted to contain mucus and blood with hypoalbuminaemia (17-29 g/l), suggesting a protein-losing enteropathy. Stools electrolytes were: Na+ 50-120 mmol/l, K+ 15-80 mmol/l, Cl 40-25 mmol/l; and the pH was neutral when checked. Reducing substances were only noticed with oral feeding.

Fig. 1
Fig. 1
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Diarrhoea was the only symptom in 27 cases (57%), whilst in 12 patients other symptoms included arthritis (n = 6), diabetes (n = 5), thrombocytopenia (n = 4), nephrotic syndrome (n = 3), dermatitis (n = 2), and anaemia (n = 2). Phenotypic abnormalities, including dysmorphic facial features and abnormal hair, were noted in nine cases (19%). Gut epithelial cell autoantibodies (aAb) were reported by 20 of 42 respondents (47%) and were further defined in some cases as against the brush border (n = 7) or cytoplasm (n = 6). Other autoantibodies were detected against smooth muscle (n = 15), nucleus (n = 10), mitochondria (n = 8), and DNA(n = 5).

Treatments are detailed in Table 3 and included, alone or in association: TPN (100%), continuous enteral feeding (81%), steroids(77%), bowel decontamination with antibiotic cocktail (57%), immunoglobulins(51%), cyclosporin (36%), azathioprine (32%), and cyclophosphamide (15%). Some treatments were continued for several years, but none were associated with recovery.

The outcome is known in 45 of the 47 children; information is missing in 2 patients who returned to their country of birth once the diagnosis was made and treatment had failed to improve their diarrhoea. Twenty-one children (47%) died at an average of 27 months of age (range 12-60, median 24 months). The cause of death was pneumonia (n = 9), sepsis (n = 9, of which 4 were catheter-related), dehydration (n = 2), and pulmonary embolism (n = 1).

Twenty-four children (53%) survived and were ages 2 to 15 years (median 6.5 years) at the time of data recording. Twenty (80%) remained dependent on artificial nutritional support, either parenteral (n = 16) or enteral (n = 4) feeds, some in association with immunosuppressive therapy (cyclosporin n = 3, azathioprine n = 2, steroidsn = 1) or immunoglobulin therapy (n = 3). The four other cases continued to receive cow's milk and gluten-free diets (n = 4), steroids (n = 4), cyclosporin (n = 1), azathioprine(n = 1), and immunoglobulins (n = 2).

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Histological Data

Age at the first biopsy ranged between 1 and 18 months. Two to six biopsies were reviewed for each patient. The interval between two biopsies was 2 to 156 months (median 15 months). All cases had villous atrophy of varying degrees with or without mononuclear cell infiltration of the lamina propria. Patients could be divided into two groups according to the histological criteria shown in Table 1 and Fig. 2. The fulfilment of at least five of the seven criteria led to an inclusion into one of the groups (I or II). Twenty four cases were placed in group I and 18 patients were placed in group II. Five remained unclassified according to the criteria set out in Table 1, and were considered separately.

Fig. 2
Fig. 2
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Clinicopathological Analysis

Comparison of the main clinical features in groups I and II(Table 4) showed no difference for sex ratio, family history and consanguinity, birth weight, initial feeding, stool output volume, and outcome. Significant differences were observed: in group I, patients were older when diarrhoea started (p < 0.01), and had a higher prevalence of protein-losing enteropathy (p < 0.05), gut autoantibodies (p < 0.05), and extraintestinal symptoms(p < 0.001), but fewer cases showed phenotypic abnormalities(p < 0.05).

Table 4
Table 4
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An additional analysis was performed for group I and II according to two main criteria that seemed to be characteristic of different clinical subgroups: (a) in group I, the presence or absence of extraintestinal symptoms suggestive of autoimmune diseases (producing groups Ia and Ib, respectively;Table 5); (b) in group II, the presence or absence of phenotypic abnormalities including facial dysmorphy and/or abnormal hair(forming groups IIa and IIb, respectively, Table 6).

Table 5
Table 5
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Table 6
Table 6
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Twelve infants (group Ia) presented with extraintestinal symptoms including arthritis, diabetes, nephrotic syndrome, dermatitis, anaemia, thrombocytopenia, and tended to have a later onset of diarrhoea, which was of larger volume (p < 0.05) compared with patients of group Ib. Group Ib only showed evidence of gastrointestinal symptoms(Table 5). One case in group Ia (number 38) showed an absence of goblet cells coincident with the presence of goblet cell autoantibodies.

Group II was subdivided into eight cases with phenotypic abnormalities(group IIa) and 10 children who presented with mucosal changes including mild to moderate villous atrophy. Abnormalities were localized mainly in the epithelium and included disorganization of surface enterocytes with focal crowding, resembling tufts, and crypts with a branching and/or pseudocystic appearance; tufting was occasionally seen in crypt epithelium (group IIb)(Table 6). Family history was noted in 30% of group IIb patients and in none of group IIa. Group IIa had a lower birth weight (1,919± 389 g versus 3,085 ± 393 g; p < 0.01).

Group III included five patients with villous atrophy in which histological analysis did not result in specific features, such as increased lamina propria cellularity or epithelial cell abnormalities, being recognised. Children were normal for gestational age, with an early onset of diarrhoea (45 ± 42 days of life, median 35 days) without protein-losing enteropathy or extraintestinal symptoms, whereas three (60%) had gut autoantibodies. Four children (80%) were alive at the time of recording, but all had been on TPN for 12 to 84 months at the time of study.

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DISCUSSION

Precise clinical and light microscopic analysis of this collection of 47 cases of intractable diarrhoea of infancy with persistent villous atrophy has allowed several distinct clinicopathological categories to be recognised within the syndrome. In the group as a whole, diarrhoea is the first clinical symptom that appears. It is abundant (123 ± 86 ml/kg/day) and persists despite bowel rest and/or therapeutic trials including steroids and/or cyclosporin A. These characteristics clearly differentiate intractable diarrhoea of infancy from protracted diarrhoea, which responds to bowel rest and/or enteral feeding and always recovers even after several weeks or months of parenteral and/or enteral tube nutrition.

The severity of intractable diarrhoea of infancy, requiring long-term TPN as well as immunosuppressive therapy with variable efficiency, can explain the high mortality rate (47%) observed in this series. The severity of the diarrhoea is also evident from the fact that 80% of the survivors remain partially or totally dependent on parenteral nutrition after several years of follow-up (2-10 years). The future course of these patients remains uncertain and could involve small-bowel transplantation (26) as already attempted in some cases of microvillous inclusion disease(27,28).

Histological analysis seems to be the most important point for the diagnosis of intractable diarrhoea of infancy. Patients in this series presented histologically in two clearly different forms that were distinguished using the criteria given in Table 1. The more severe histological picture in group 1 (in terms of villous atrophy, crypt hyperplasia, and lamina propria cellular infiltration) was associated with a later onset of diarrhoea and a higher prevalence of extradigestive symptoms, gut epithelial cell autoantibodies, and protein-losing enteropathy. Additional clinicohistological analysis demonstrated that the groups could be further divided, allowing a total of four different groups to be delineated.

Groups Ia and Ib are characterized by a mononuclear cell infiltration of the lamina propria and may be considered to be associated with activated T cells and epithelial injury, as previously reported (24). Villous atrophy is moderate to severe and associated with crypt hyperplasia, epithelial cell necrosis, and crypt abscess formation. The surface epithelium is reduced in height with dedifferentiated and basophilic cells. The number of goblet cells is reduced and in some cases, none or very few goblet cells could be recognised (29,30). It has been shown in similar cases that mononuclear cell infiltration within the lamina propria includes mainly CD4+ T lymphocytes and macrophages; numerous cells express CD25, whereas HLA-DR expression is increased on crypt epithelium(24). These changes are largely observed in small-bowel mucosa, but it seems very important to look for such phenomena in other segments of the digestive tract, such as the colon (31) and stomach. When involved, they show the same type of lesions including epithelial cell necrosis, crypt abscess formation, and mononuclear cell infiltration of the lamina propria. The present study reviewed only small-bowel mucosa without immunohistochemical staining, and could not confirm this point. Nevertheless, the presence and characteristics of mucosal injury in group Ia and Ib patients suggest a T-cell activation mechanism such as described in coeliac disease, graft-versus-host disease, or small-bowel graft rejection (32-36). In groups Ia and Ib, there is a variable and sometimes absent response to immunosuppressive treatment including steroids, cyclosporin, cyclosphosphamide, or azathioprine. A few cases of a beneficial effect of cyclosporin have been reported(14,37). It is possible that a better response will come from FK506 treatment (38).

Group Ia, which included patients with extraintestinal manifestations of autoimmunity, seems to correspond to previously reported cases of autoimmune enteropathy(2-20). Onset of diarrhoea is usually several months after birth and is associated with extraintestinal manifestations such as arthritis, diabetes, dermatitis, thrombocytopenia, and renal disease. Villous atrophy seems to be more pronounced, with severe crypt damage including necrosis and abscess formation. The high male incidence in previously reported cases of autoimmune enteropathy(2-13) was not confirmed by this study.

Circulating gut epithelial `cell autoantibodies are positive most of the time in groups Ia and Ib. They are primarily IgG and indirect immunofluorescence has shown that they are directed against components of the brush border or cytoplasm of the enterocytes of normal small-bowel mucosa(4-6,9), although goblet cell autoantibodies have been detected (29,30). Other associated autoantibodies are mainly directed against the nucleus, DNA, smooth muscle, or mitochondria. The significance and precise role of gut autoantibodies in the pathogenesis of the disease remain unknown, although the partial response to cyclosporin A (14,37) and the promising use of FK506 (38) indicates that T cells may be more important in the pathogenesis of this disorder. Finally, the two groups(Ia and Ib) may be different or may correspond to a different degree of expression of the same mechanism involving activation of intestinal mucosal T cells. The presence of extraintestinal symptoms may be due to the presence of shared epitopes between tissues producing cross-reacting autoimmunity. The mechanisms by which activated T cells are responsible for epithelial damage could be via a direct cytotoxic action, lymphokine release and/or recruitment, and activation of macrophages. It would be worthwhile to study the intestinal T-cell repertoire to investigate the existence of autoreactive intestinal T lymphocytes.

Group IIb includes severe intractable diarrhoea with villous atrophy but without mononuclear cell infiltration of the lamina propria. These cases presented during the neonatal period (median onset 7 days) with severe watery diarrhoea. Forty percent of the patients have consanguineous parents and/or affected siblings who died during the first months of life with severe diarrhoea of unknown origin. Villous atrophy is always present but variable in severity. Abnormalities are localized mainly in the epithelium and appear similar to those described as “tufting enteropathy” by Reifen et al. (39) In some infants of this group, abnormal laminin and heparin sulfate proteoglycan deposition on basement membrane has been reported, i.e., faint and irregular laminin deposition at the epithelial-lamina propria interface, while heparin sulfate proteoglycan appeared widened and lamellar (40). Basement membrane molecules are involved in epithelial-mesenchymal cell interactions, which are instrumental in intestinal development and differentiation(41-43). More recent data show alterations suggestive of cell-cell and cell-matrix interactions. They include abnormal distribution of α2β1 integrin along the cryptvillous axis, an increased immunohistochemical expression of desmoglein, and ultrastructural changes of desmosomes that were increased in length and number(44). Whether these modifications are primary or secondary remains to be determined, but they might be related to epithelial abnormalities and to the severity of this neonatal diarrhoea, which resists all treatments and requires permanent parenteral nutrition(40).

Six of the patients included in group IIa have already been published(45). Patients in this group presented with diarrhoea starting in the first 6 months of life (less than 1 month in six cases) and have several features in common. All were small for gestational age (<2,000 g at 39-41 weeks of gestational age) and had facial dysmorphism, hypertelorism, and wooly, easily removable hair with trichorrhexis nodosa(45). In addition, the previously reported patients had defective antibody responses, despite normal serum immunoglobulin levels, and defective antigen-specific skin tests despite positive proliferative responses in vitro. Small-bowel biopsy specimens of the patients of group IIa showed moderate or severe villous atrophy with a variable mononuclear cell infiltration of the lamina propria and absence of epithelial abnormalities. One patient of group I also had intrauterine growth retardation with phenotypic abnormalities but had increased lamina propria mononuclear cells. Prognosis of this type of intractable diarrhoea of infancy is poor, because five patients died between the ages of 2 and 5 years. The cause of this diarrhoea is unknown, and the relation between low birth weight, dysmorphism, severe diarrhoea, trichorrhexis, and immune deficiency is unclear. These features may constitute a specific syndrome within this series of intractable diarrhoea of infancy.

When confronted with the diagnosis of intractable diarrhoea of infancy, clinical and histological data should be taken into account. Such an analysis may allow a broad classification, even in the absence of immunohistochemical studies. The main clinical criteria that should be considered are: birth weight, familial history, date of onset and characteristics of diarrhoea(watery and/or bloody, persistent despite bowel rest), the existence of extradigestive manifestations, the presence of gut and/or other autoantibodies, and the existence of phenotypic abnormalities. Protracted diarrhoea of infectious origin and/or immune deficiency have to be eliminated. Microvillous atrophy/inclusion disease can be excluded by performing periodic acid-Schiff staining and electron microscopy(22,23). Table 7 summarises the features of distinctive disorders within the syndrome of intractable diarrhoea with persistent villous atrophy. Routine light microscopy of small-bowel biopsy specimens affords the detection of all the histological features described in this article.

Table 7
Table 7
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In conclusion, this provisional classification is probably incomplete, because other forms of intractable diarrhoea of infancy with abnormal small-bowel mucosa have been described (46,47). However, it indicates that there are different pathogenetic mechanisms operating in the clinical groups and may allow specific treatment to be pursued. In addition, it forms a basis for future research in this exceptionally difficult paediatric condition.

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ASSOCIATED COLLEAGUES

We are extremely grateful to the colleagues listed below, who responded to the survey, provided histological material for analysis, and made the study possible.

Dr. I. Alvares, Hospital Ramon Y Cajal, Madrid, Spain.

Dr. J. Amil Dias, St. John's Hospital, Porto, Portugal.

Dr. P. Baehler, Children's Hospital, University of Berne, Switzerland.

Dr. A, Barabino, Paediatric Division, G. Gaslini Institute, Genova, Italy.

Dr. L. Boccon-Gibod, Trousseau Hospital, Paris, France.

Dr. J. Bouquet, Sophia Children's Hospital, Rotterdam, The Netherlands.

Dr. M. J. Brueton, Westminster Children's Hospital, London, U.K.

Dr. Burke, Royal Berkshire Hospital, Reading, U.K.

Dr. C. Camareo, Hospital Ramon y Cajal, Madrid, Spain.

Dr. F. Carrazza, Children's Nutrition Research Centre, Baylor Medical College, Houston, U.S.A.

Pr. J. P. Cézard, Hopital Robert Debré, Paris, France.

Pr. A. M. Colombo, Ospedale Bambino Gesu, Rome, Italy.

Dr. J. Dodge, University Hospital of Wales, Cardiff, U.K.

Dr. D. Faraguna, Burlo Garofalo Children's Hospital, Trieste, Italy.

Pr. J. L. Fontaine, Trousseau Hospital, Paris, France.

Dr. J. P. Girardet, Trousseau Hospital, Paris, France.

Dr. A. Guarino, University Children's Hospital, Naples, Italy.

Dr. Hardy, Herts & Essex Hospital, Bishop Stortford, U.K.

Dr. P. Heinz-Erian, Department of Paediatrics, University of Munich, Germany.

Dr. E. Isolauri, Tampere University Hospital, Tampere, Finland.

Dr. K. M. Keller, Johannes Gutenberg University Children's Hospital, Mainz, Germany.

Dr. P. Küster, University Children's Hospital, Essen, Germany.

Dr. P. de Magalhaes Ramalho, Faculty of Medicine, Lisbon, Portugal.

Dr. J. McKiernan, Cork Regional Hospital, Cork, Ireland.

Dr. N. J. Meadows, Queen Elizabeth Hospital for Children, London, U.K.

Pr. J. Navarro, Hopital Robert Debré, Paris, France.

Dr. B. L. Nichols, Children's Nutritiòn Research Centre, Baylor Medical College, Houston, U.S.A.

Pr. W. Nutzenadel, Ruprecht-Karls University Children's Hospital, Heidelberg, Germany.

Dr. T. Ormala, University of Helsinki Children's Hospital, Helsinki, Finland.

Dr. F. Pesce, Paediatric Division, G. Gaslini Institute, Genova, Italy.

Pr. C. Ricour, Hopital des Enfants Malades, Paris, France.

Dr. E. Savilahti, University of Helsinki Children's Hospital, Helsinki, Finland.

Dr. L. S. Taitz, Children's Hospital, Sheffield, U.K.

Dr. J. Vanderhoof, Creighton University Medical Centre, Nebraska, U.S.A.

Dr. P. Vassallo-Agires, St. Luke's Hospital, Guard-amangia, Malta.

Dr. A. Ventura, Burlo Garofalo Children's Hospital, Trieste, Italy.

Dr. Ware, Rochford Hospital, Rochford, U.K.

Pr. C. B. S. Wood, Queen Elizabeth Hospital for Children, London, U.K.

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Keywords:

Autoimmunity; Intractable diarrhoea; Phenotypic abnormalities; Villous atrophy

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