Congenital Constitutive Diarrheal Disorders

Clinical Considerations

The typical clinical picture is abundant watery, sometimes mucous diarrhea starting within the first hours or days of life [2, 3]. Diarrhea can be so important that within a few hours a rapidly life-threatening situation develops due to massive dehydration and metabolic acidosis. The neonatal course (presence or absence of polyhydramnios) presents essential information contributing towards the differential diagnosis of a secretory (chloride or sodium) diarrheal disorder if polyhydramnios is present or a constitutive enterocyte disorder (absence of polyhydramnios). A major step in the differential diagnosis of congenital or early onset watery diarrhea is the response to complete bowel rest, as well as the determination of fecal and serum electrolytes. If diarrhea stops on total bowel rest it is most likely secondary to malabsorption or malassimilation (fig. 1), whereas, once defects in electrolyte transports are eliminated, massive and persistent diarrhea indicates a constitutive enterocyte disorder, such as MVA/MVID or intestinal epithelial dysplasia (IED)/TE or rarely syndromatic or phenotypic diarrhea.

In MVA/MVID, severe watery diarrhea typically starts within the first days of life [2-4]. This diarrhea becomes so abundant that within 24 h children can lose up to 30% of their body weight, resulting in profound metabolic acidosis and severe dehydration. MVID is most often severe and life-threatening. Accurate quantification of stool volumes reveals 150 to over 300ml/kg/day with a high sodium content (over 100mmol/l). Complete and prolonged bowel rest makes it possible to reduce stool volume moderately, but it nearly always remains above 150ml/kg/day [4]. Typically, no additional clinical signs are associated with MVID; in particular, there are no malformations or involvement of other organs such as liver or kidney. However, a small number of children have massive pruritus secondary to elevated concentrations of biliary acids in the blood. Also, proximal renal tubular dysfunction was observed in some children with MVID/MVA. At clinical examination, no specific findings can be detected except enormous abdominal distension with fluid-filled intestinal and colonic loops. All children with congenital MVID urgently require total parental nutrition, which often causes rapidly evolving cholestasis and liver disease. A detailed multicenter analysis of 23 patients with MVID [4] distinguished two different forms and presentations of MVID on a clinical and morphological basis: the most frequent form, that is congenital early-onset MVID (starting within the first days of life), and some rare cases, that is late-onset MVID (with first symptoms appearing after 2 or 3 months of life). Intestinal failure is definitive in all children with early-onset

MVID and most with late-onset MVID. Some rare children with late-onset MVID were described who had a somewhat less severe course. In general, children with MVID are potential candidates for small bowel transplantation [5].

In IED/TE, massive watery diarrhea develops within the first days after birth in a way similar to MVA/MVID. Stool volumes are highly variable (100-200 ml/kg body weight/day) with stool electrolyte concentrations of sodium of 100-140 mmol/l [6, 7]. All children are highly dependent on par-enteral nutrition. There is no past history of hydramnios or other antenatal or neonatal particularities. It is striking that in our experience most children with IED/TE have consanguineous parents and/or affected siblings and some of them died during the first months of life with severe diarrhea of unknown origin. Upon clinical examination, no malformations are observed; however, some children have somewhat rigid hair and a subgroup of patient shows clinical signs of photophobia. Distinct ophthalmologic examination reveals the presence of superficial keratitis in these children. The degree of severity of IED/TE is more variable compared to MVA/MVID with most children developing a severe course indicating lifelong and definitive intestinal failure. However, some patients have less severe disease and may acquire a certain degree of intestinal autonomy making it possible to reduce parenteral nutrition to three to four perfusions a week.

A distinct clinical group is the so-called phenotypic or syndromatic diarrhea. This disorder, first described by the group of Goulet [8] in Paris, is characterized by small for gestational age babies with severe persistent watery diarrhea associated with an abnormal phenotype, including facial dysmor-phism, hypertelorism, and woolly, easily removable hair with trichorrhexis nodosa. In addition, immunological abnormalities were observed in all patients in the form of defective antibody responses despite normal serum immunoglobulin levels, and defective antigen-specific skin tests despite positive proliferative responses in vitro. The majority of patients followed in our center were the progeny of consanguineous marriages. The clinical course of these children is variable. Most of the children died in the past, but some of the survivors acquired a certain degree of intestinal autonomy.

Molecular Considerations

There is strong evidence that all these congenital/early-onset structural ente-rocyte disorders have a distinct genetic basis [2]. The clinical features suggest an autosomal recessive transmission. Since the gene(s) involved are not yet identified for these congenital inherited autosomal recessive diseases, no genetic or prenatal diagnosis is possible. The majority of children with MVA/MVID are of Turkish origin; however, we follow up a couple of children with MVA/MVID (most with several affected siblings) of Caucasian origin. Patients with IED/TE are most often of Arab origin, that is Middle East including Turkey or North Africa. The prevalence in Malta Island, in the Mediterranean Sea, seems high but the phenotype might be milder. Once again, a small number of IED patients

Atrophy Microvilli
Fig. 2. MVA/MVID: electron-microscopic picture showing typical atrophic microvilli on a mature IEC of the duodenum as well as microvillous inclusions (asterisk).

followed up in our center are also of Caucasian origin without any evidence of consanguinity, indicating sporadic de novo mutations.

The precise molecular basis of MVA/MVID is still unknown. There is evidence of a major defect in membrane trafficking in intestinal epithelial cells (IEC), probably secondary to an altered structure of the cytoskeleton [9]. This disorder is morphologically characterized by the occurrence of so-called microvillous inclusions at the apical pole of enterocytes along with absent or atrophic microvilli on mature enterocytes easily visible on electron-microscopic analyses (fig. 2). The observation of morphologically normal microvilli on immature crypt cells in children with MVID indicates that the microvillous changes seen in differentiating and mature cells are of secondary nature or they are a consequence of yet unidentified events within the cell, such as membrane recycling or mechanisms controlling endo- or exocytosis [10, 11]. However, analysis of the membrane targeting of the disaccharidase sucrase-isomaltase revealed no abnormalities of the direct or indirect constitutive pathway. Another hypothesis suggesting a defect in the autophagocy-tosis pathway was proposed to explain the morphological and functional abnormalities in MVID. Very recent observations indicate a selective defect in glycoprotein exocytosis in patients with MVID [12]. These glycoproteins accumulate within the apical pole of enterocytes and form the characteristic secretory granules, easily observed on PAS staining on duodenal sections of patients with MVA/MVID (fig. 3).

In contrast to MVA/MVID which is most likely the consequence of an IEC membrane trafficking defect, IED/TE results from a regulatory defect of epithelial mesenchymal cell interactions, which are instrumental in intestinal development and differentiation. Alterations suggestive of abnormal cell-cell and cell-matrix interactions were seen in patients with IED without any evidence of abnormalities in epithelial cell polarization and proliferation [13].

Fig. 3. MVA/MVID: high-power magnification of a duodenal section after periodic acid-Schiff (PAS) staining or anti-CD10 immunohistochemistry. As shown on both panels compared to normal controls, in MVA an enlarged intracytoplasmic band (arrow) at the apical pole of enterocytes can be seen along with an atrophic band instead of the normally well-defined small line representing the brush border (asterisk).

Fig. 3. MVA/MVID: high-power magnification of a duodenal section after periodic acid-Schiff (PAS) staining or anti-CD10 immunohistochemistry. As shown on both panels compared to normal controls, in MVA an enlarged intracytoplasmic band (arrow) at the apical pole of enterocytes can be seen along with an atrophic band instead of the normally well-defined small line representing the brush border (asterisk).

These alterations included abnormal distribution of the adhesion molecule a2pi integrin along the crypt-villous axis. The a2pi integrin is involved in the interaction of epithelial cells to various basement membrane components, such as laminin and collagen. To date, the pathophysiological mechanisms resulting in an increased immunohistochemical expression of desmoglein and the ultrastructural changes of desmosomes are unclear [13]. A major morphological feature of IED is the occurrence of epithelial tufts at the villi, along with crypt branching (fig. 4). Tufts correspond to rounded epithelial cells at the villous tips that are no longer in contact with the basement membrane. It can be speculated that a defect of normal enterocyte apoptosis at the end of their lifespan or an altered cell-cell contact is responsible for this effect. The primary or secondary nature of the formation of tufts remains to be determined. Mice with a disrupted gene encoding the transcription factor Elf3 display morphologic features resembling IED [14]. In this model, an abnormal morphogenesis of the villi was observed while progenitor crypt cells appear normal. IEC are characterized by a low transforming growth factor-p type 2 receptor expression, which is implicated in the differentiation of immature IEC.

Fig. 4. IED or TE: partial villous atrophy with crypt hyperplasia and/or pseudocystic crypt appearance, branching pictures and disorganization of surface epithelium with typical tufts (arrow).

The molecular basis of phenotypic syndromatic diarrhea is completely unknown. The diagnosis of this syndrome is made by the association of different clinical symptoms. Characteristic or pathognomic histological alterations of the intestinal mucosa were not observed. Marked (subtotal to total) villous atrophy on duodenal biopsies along with a variable inflammatory infiltrate of the lamina propriety is seen in the majority of patients. In a recent study, we did not observe an increased expression of HLA molecules on IEC. To date, the genetic basis of this disorder remains unclear.

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