Intractable diarrhea in infancy and molecular analysis: We are beyond the tip of the iceberg.

BACKGROUND: Intractable diarrhea (ID) could be defined as a syndrome of severe chronic diarrhea associated with malnutrition not easily resolved by conventional management. AIMS: To provide an overview on etiology and management of ID patients in Italy in the last 12 years. METHODS: The members of Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) enrolled all ID patients seen between January 1, 2011 and December 31, 2022. RESULTS: 69 children were enrolled (49 M, 20 F; median age at ID onset 9.5 days) from 7 tertiary care pediatric centers. Overall 62 patients had genetic diseases; 3 had infantile Inflammatory Bowel Disease and 1 autoimmune enteropathy in absence of genetic mutations; 2 undefined ID. Defects of intestinal immune-related homeostasis caused ID in 29 patients (42 %). CONCLUSION: ID is a rare but challenging problem, although the potential for diagnosis has improved over time. In particular, molecular analysis allowed to identity genetic defects in 90 % of patients and to detect new genetic mutations responsible for ID. Due to both the challenging diagnosis and the treatment for many of these diseases, the close relationship between immune system and digestive tract should require a close collaboration between pediatric immunologists and gastroenterologists, to optimize epidemiologic surveillance and management of ID.

Ductopenia and fetal liver-like architecture as unique and evocative sign of Turner syndrome.

BACKGROUND: Turner syndrome is the most common genetic disorder in females. In most subjects, with a normal physical appearance at birth, the diagnosis is suspected long after birth because of short stature, delayed puberty, primary or secondary amenorrhea or infertility. Abnormalities of liver function tests are reported in literature, with a prevalence ranging from 20% to 80%. In most subjects liver diseases are self-limiting, associated with obesity, hormonal therapy and autoimmune diseases. An association between Turner syndrome and cryptogenic liver disease has been reported. Abnormalities of liver function tests could be the unique sign of Turner syndrome in subjects with normal phenotypes. The histological picture of "fetal liver-like architecture" and "ductopenia" is of fundamental importance for the diagnosis of chromosomopathy. AIM: Review the causes of hypertransaminasemia by focusing on more rare as metabolic and genetic diseases. MATERIALS AND METHODS: We evaluated a 10 year old girl with a normal phenotype affected by chronic hypertransaminasemia and cholestasis, in whom a needle liver biopsy was performed after the most common causes of hypertransaminasemia were excluded. RESULTS: Liver histological evaluation revealed a smoldering colangiopathy with mild ductopenia and a fetal liver-like architecture. Turner syndrome, suspected on the basis of this histological picture, was confirmed by a pelvic ultrasound and a chromosome analysis. CONCLUSIONS: The histological features of "fetal liver-like architecture" and "ductopenia" represent an evocative sign that could indicate the diagnostic suspicion of Turner syndrome in a subject lacking in signs or symptoms of this disease. It is important to perform a pelvic ultrasound and an endocrinological evaluation in all females with chronic asymptomatic hypertransaminasemia even though they have normal phenotypes.

ERCP with intracholedocal biopsy for the diagnosis of biliary tract rhabdomyosarcoma in children.

Rhabdomyosarcoma is the most common tumor of the biliary tract in children. Although some features at preoperative radiographic studies (ultrasound, CT, MRI) may be suggestive of BT-RMS, until few years ago the final diagnosis was obtained by either operative or transcutaneous biopsy, thus exposing to a risk of regional dissemination. More recent and still anecdotal, is the histological diagnosis on tissue obtained by transluminal biopsy either during transhepatic cholangiography or endoscopic retrograde cholangio-pancreatography (ERCP), the latter having the major advantage of a much lower risk of loco-regional dissemination. We present two cases of BT-RMS that were histologically diagnosed by intracholedocal biopsy performed during ERCP, after being suspected at conventional imaging.

Liver transplantation for refractory severe pruritus related to widespread multifocal hepatic focal nodular hyperplasia (FNH) in a child: case report and review of literature.

FNH is a rare and benign tumor of the liver. It is not a conventional indication for liver transplantation, and no transplant for FNH in a child has been reported to date. Multifocal FNH growing in adolescent age to a widespread tumor invading the whole liver and associated with severe refractory pruritus was an unusual indication for transplantation in a 13-yr-old girl. The operation and the follow-up were uneventful, allowing full recovery and disappearance of pruritus.

A case of a mild Wolfram Syndrome with concomitant ATP7B mutation.

BACKGROUND: Wolfram Syndrome 1 (WS1) has been characterized on the basis of mutation in the WFS1 gene encoding a calcium storage wolframin endoplasmatic reticulum transmembrane glycoprotein. PATIENTS AND METHODS: We observed a WS 10-years old female subject, with Type 1 diabetes-mellitus (DM), that had compound heterozygous WSF1 mutations but without other symptoms generally observed in WS subjects, such as optic atrophy or neurodegeneration. RESULTS: Decreased copper, ceruloplasmin, and transferrin levels, pointing to a copper deficiency, were associated with a new c.18703A>G mutation in the ATP7B gene, while lower calcium levels were associated with WSF1 mutations. An omega-3 fatty acids therapy was administrated to the subject in the attempt to ameliorate diabetes symptoms, restored copper deficiency, and normal calcium levels. CONCLUSIONS: This specific case report provides new insights into the potential interplay of ATP7B mutation in shaping a milder WS clinical picture.

Low molecular weight heparin as cause of liver injury: case report and literature review.

Low molecular weight heparins (LMWH) are a class of drugs including various molecules that inhibit predominantly the factor V of coagulation and are used in a wide range of clinical settings for the management of venous thromboembolism and acute coronary syndrome. Despite LMWH are considered safe and associated with a lower incidence of side effects compared to unfractioned heparin, it is worth considering that the use of LWMH can be associated with complications. Some of these, such as bleeding and thrombocytopenia, are well-known, whereas other ones are often underestimated leading to a diagnostic delay. In this case report, we describe a case of a 73-years-old man who recently started nadroparin for deep vein thrombosis presenting with acute hepatitis. The diagnostic workup of drug-induced liver injury (DILI) requires the exclusion of other causative agents and temporal association between the initiation of the culprit drug and hyper aminotransferasemia. This clinical case analyzes how to deal with a suspicion of DILI and consider LWMH as a potential cause of DILI, which requires a modification of the anticoagulant treatment.

Arterial changes in children undergoing renal transplantation.

INTRODUCTION: Pathological changes of large arterial walls and the heart have been described in patients with chronic renal failure. The aim of the study was to verify the incidence of arterial changes among our series of pediatric patients with end-stage renal disease undergoing transplantation. PATIENTS AND METHODS: From January 2004 to December 2006, 26 patients (15 boys and 11 girls) of overall mean age of 13.12 years (range=3-27 years) underwent renal transplantation in our department. The pretransplant dialysis treatment was peritoneal in eight and hemodialysis in 18 cases. All patients were divided in two groups according to primary renal disease: group A were 18 patients with congenital urinary malformations; and group B, eight patients with acquired glomerular diseases. In each case, a sample of artery from both donor (aortic patch of kidney) and recipient (iliac patch of graft allocation) was obtained during renal transplantation. The donors were considered to be the control group. RESULTS: Light microscopy showed pathological changes in 12/26 recipient arteries: nine showed light fragmentation of the internal elastic lamina; two, more severe fragmentations; and one, fragmentation of the internal elastic lamina associated with mucopolysaccharide deposits. Pathological changes were more evident in group A than B, but the difference was not significant (P> .05). Among the donor group, 11 patients showed light fragmentation of the internal elastic lamina, but there was no significant difference with the recipients (P> .05). CONCLUSIONS: Among our group of patients, we observed only slight modifications of the arterial wall. These changes were nonspecific, similar to those in a control group of donors matched for age. A possible explanation of these findings may depend on the short time of dialysis before transplantation.

Fatal infantile leukodystrophy: a severe variant of CACH/VWM syndrome, allelic to chromosome 3q27.

OBJECTIVE: To describe clinical and neuropathologic studies and linkage analysis on two sisters with a severe form of leukodystrophy. METHODS: A detailed study was performed on the second sister. Genotyping markers for chromosome 3, including eight additional markers surrounding the vanishing white matter (VWM) locus, were used. RESULTS: During the first year of life, two sisters developed a severe neurologic condition after an intercurrent infection. It was accompanied by irritability and stupor with rapid loss of their motor abilities. Results of extensive metabolic studies were negative. Brain MRI showed severe and diffuse abnormalities of the encephalic white matter. Neuropathologic examination showed a severe lack of myelin with diffuse vacuolating white matter lesions in the brain, associated with an increased density of oligodendrocytes and a reduced number of astrocytes on morphometric analysis. In sharp contrast, the spinal cord white matter was preserved. The affected sibpairs shared a common haplotype for a broad region in chromosome 3. They were homozygous between markers D3S1565 and D3S3669, including the VWM locus. CONCLUSIONS: This condition is an unusual variant of childhood ataxia with diffuse central hypomyelination (CACH)/VWM, with characteristic shrinking and perivascular clustering of astrocytes. Haplotype analysis suggests that this variant is allelic to the VWM locus located on chromosome 3q27.

A genetic assessment of trisomy 21 in a patient with persistent truncus arteriosus who died 38 years ago.

A newborn baby with the unique combination of Down syndrome and persistent truncus arteriosus with interrupted aortic arch is described. The diagnosis of trisomy 21 was assessed 38 years after the patient's death by means of fluorescent in situ hybridization.

The pattern of desmin filaments in myocardial disarray.

"Myofiber disarray" defines a nonparallel arrangement of cardiac myocytes. The presence of a sufficient quantity of myocardial fibers showing this change is considered to be a specific histological feature of hypertrophic cardiomyopathy (HCM). However, small zones of myofiber disarray are found in both cardiac hypertrophy and other pathological conditions. Recently, we demonstrated an altered pattern of desmin intermediate filaments in disarrayed myofibers from specimens of HCM. To test the hypothesis that desmin alterations might be specific for cardiomyopathy, we performed an immunohistochemical study on myocardial surgical samples from 11 patients with HCM and from 12 patients with tetralogy of Fallot (toF) on 14 endomyocardial biopsy specimens (EMBs) from transplant recipients with myofiber disarray surrounding areas of scarring (previous biopsy site) and on specimens of four autoptic hearts with severe acquired left ventricular hypertrophy. Disarrayed myofibers from all specimens of HCM showed the following abnormalities in the pattern of desmin intermediate filament distribution: (1) decrease or loss of labeling of intercalated discs and Z bands, (2) longitudinal arrangement of desmin intermediate filaments, and (3) intense, granular staining of several myocytes. This spectrum of desmin alterations was never observed in disarrayed myofibers in specimens of toF or acquired myocardial hypertrophy or in EMBs. Altered distribution of desmin intermediate filaments seems to be specific to myofiber disarray in HCM and it may play a role in the altered myocyte arrangement in HCM.

Working formulation nomenclature of heart transplant pathology: A retrospective evaluation of 1037 endomyocardial biopsies.

Working Formulation (WF) was recently introduced by the International Society for Heart Transplantation to grade acute cellular rejection, as well as additional lesions observed in endomyocardial biopsies (EMBs). The aim of this study was to evaluate the actual advantages of this grading system in terms of feasibility and predictive value. To this purpose, we reclassified 1037 EMBs performed in our heart transplantation units according to the WF. Our results show that multifocal mild rejection (grade IA), when worsening, tends to progress to multifocal moderate (3A), whereas diffuse mild (1B) generally worsens to diffuse moderate (3B), thus following the same focal or diffuse pattern. Unifocal moderate rejection (grade 2) has a peculiar behavior, in that it almost always resolves, though in our units it is treated the same way as is grade 113. Finally, we found a significant relationship between Quilty B effect and chronic rejection. In conclusion, this retrospective study shows that WF is effective in using both qualitative and quantitative criteria and, particularly, in separating focal and diffuse forms of rejection and devoting a distinct grade to unifocal moderate rejection.

Morphology of the atrioventricular valve in asplenia syndrome: A peculiar type of atrioventricular canal defect.

The high risk of atrioventricular (AV) valve regurgitation is a major point of concern in the natural history of patients with atrioventricular canal defect (AVCD) and asplenia syndrome (AS). The morphology of the common AV valve in patients with AVCD and AS was therefore studied and compared with the anatomy of patients with AVCD but with atrial situs solitus. We compared the anatomic features of hearts with common AV valve (ventricular loop; AV valve alignment on ventricles; number of leaflets; number and morphology of papillary muscles and relationship of the bridging leaflets with the ventricular septum) in the hearts of 33 patients with AVCD and asplenia syndrome (Group 1) with those of 44 patients with common AV valve, complete AVCD, and atrial situs solitus (Group 2). Hearts featuring asplenia syndrome showed a significantly higher occurrence of anomalies of the ventricular loop (p < .0001), right ventricular dominance (p < .01), and a reduced number of valvular leaflets and papillary muscles (p < .0005). On the contrary, hearts with situs solitus of the atria showed a significantly higher frequency of balanced ventricles (p < .0001) and a common AV valve with five leaflets and five papillary muscles (p < .000001). These data suggest that AVCDs in association with asplenia syndrome present morphologic peculiarities that may be considered as the substrate for the abnormal regurgitation. Recognizing the presence of these features could be of great value for the planning of a specific surgical treatment. These anatomic differences support the hypothesis of a genetic heterogeneity of AVCDs.

Pathology of atrioventricular valve dysplasia.

The congenital heart disease series of the Pathological Museum at La Sapienza University of Rome was revised in order to detect specimens featuring atrioventricular valve dysplasia (AVVD) in fetuses and infants. Selected for study were 67 specimens from a collection of 667 hearts: there were 36 cases of isolated tricuspid valve dysplasia (TVD), 11 cases of isolated mitral valve dysplasia (MVD), and 20 cases of combined atrioventricular valve dysplasia. All the valves were graded according to Becker's criteria, which were morphometrically validated. There is an increasing degree of dysplasia in terms of differentiation and detachment of the valve from the ventricular wall. The concept of AVVD is supported by a substantial morphologic and morphometric analogy between TVD and MVD, in spite of some peculiarities of each grade and of side-specific anomalies ("mitral arcade" on the left side and grade III dysplasia on the right one), probably attributable to differences in the embryonic development of the two valves. AVVD is sometimes associated with dysplasia of the semilunar valves, in the setting of a polyvalvular disease of possible genetic origin. More often it is combined with other defects that cause ventricular overload. In such cases, AVVD usually occurs within the overloaded cardiac section, as if it were a result of mechanical stress.

Left ventricular outflow tract obstruction in atrioventricular septal defects: a pathologic and morphometric evaluation.

Subaortic stenosis has been described with increasing frequency as an ominous feature of atrioventricular septal defect (AVSD), especially following surgical correction of the anomaly in non-Down's syndrome patients. In order to study the surgical anatomy of the left ventricular outflow tract in this malformation, 48 hearts featuring AVSD were examined. Obstructive lesions were classified into unequivocal forms (class A, 13.5%) and potential ones (class B, 10.8%). In the remaining hearts (class C, 75.7%) no obstruction was noted. In class A, subaortic stenosis was due to exaggeration of the anticipated anomalous arrangement of atrioventricular valve tensor apparatus, to the persistence of a subaortic muscular infundibulum, and to a discrete fibrous diaphragm. A potential for subaortic stenosis is provided by the unwedged position of the aortic valve. The left ventricular outflow tract is transformed into a long, forward-displaced fibromuscular channel. Morphometric analysis showed in AVSD (with both common annulus and separate orifices) a significantly (p less than 0.01) lower inflow/outflow tract ratio, and a significantly (p less than 0.01) lower right ventricular/left ventricular outflow length ratio than normal hearts. These results suggest that AVSD is characterized not only, as commonly stated, by inflow tract shortening, but by outflow tract lengthening as well. On these anatomical grounds, nearly all cases of AVSD could harbor the potential for subaortic stenosis; however, this becomes a real hazard (class B) only when associated with forward displacement of the left anterior papillary muscle, or direct insertion on the ventricular septum of the anterior bridging leaflet, and it may be converted to an actual obstruction by the effects of surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of electrogastrography in detecting motility disorders in children affected by chronic intestinal pseudo-obstruction and Crohn's disease.

Gastrointestinal motility disorders are frequently found in several pathologies. The aim of this study was to assess, by means of electrogastrography, the presence of gastrointestinal motility abnormalities in children affected by Crohn's disease (CD) or Chronic Intestinal Pseudo-Obstruction (CIPO). Patients and Methods. We studied 34 subjects; 20 control subjects (M = 15, mean age = 10 +/- 3.5 yrs), 8 patients (M = 4, mean age = 18 +/- 7 yrs) with Crohn's disease in a quiescent phase and 6 patients (M = 6, mean age = 10 +/- 3.5 yrs) with Chronic Intestinal Pseudo-Obstruction. Results. Analysis of gastric electrical activity (GEA) parameters demonstrated that in the control group physiological post-prandial changes are represented by an increase of 3 Cycles Per Minute (3 CPM) activity, Period Dominant Power (PDP) and Period Dominant Frequency (PDF) and by the reduction of bradygastria. Crohn patients showed an insignificant increase of 3 CPM and PDP; CIPO patients showed an abnormal variation of 3 CPM, PDP and post-prandial bradygastria. Moreover, CD patients showed a significant difference in post-prandial values of PDP compared to normal subjects. CIPO patients revealed a significant difference in the values of either preprandial PDF with tachygastria or the post-prandial value of 3 CPM, compared to normal subjects. Conclusions. EEG is a non-invasive method to study gut motility related to GEA alterations present in CIPO as well as in CD patients.

[Considerations on the pathogenesis, diagnosis and therapy of renal venous aneurysm]. / Considerazioni di patogenesi, diagnosi e terapia degli aneurismi venosi renali.

An aneurysms of a renal vein is very uncommon an entity and even more so when a visceral vein is affected. The venous aneurysms are generally asymptomatic and are detected either at post-mortem examination or by Echography, CT scan or MR investigation. Occasionally they become symptomatic because of rupture, thrombosis and embolism, but even in those cases they are difficult to be diagnosed and can be life threatening particularly when bleeding occurs. Exceptionally an aneurysm of a visceral vein is an unexpected intraoperative finding and is detected during an abdominal procedure undertaken for other pathology. In our experience a true aneurysm of the main trunk of the left renal vein was detected during a procedure of aorto-bifemoral by-pass graft repair for chronic aorto-iliac occlusive disease. The aneurysm was resected and the vein repaired by direct suture. Congenital weakness of the vein wall was very likely the cause as suggested by the extreme thinness and media atrophy of the aneurysm and normal appearance of the wall of renal vein and inferior vena cava. Differences between varices and aneurysms of the renal veins are discussed as well as indications for surgical treatment.

Thalidomide as rescue therapy for acute severe ulcerative colitis.

INTRODUCTION: Acute severe exacerbations of Ulcerative Colitis (UC) represent a medical emergency in children and adults. Intravenous steroids remain the first line therapy for this condition, although the steroid refractoriness is common. Second-line therapy, based on the infliximab or thiopurines should be started if no response to corticosteroids is noted. The use of infliximab in children with acute severe UC, nevertheless, does not avoid the colectomy in all cases. METHODS: We present a case of severe acute UC in a paediatric patient successfully treated with thalidomide following the failed treatment with infliximab and a review of the literature. CONCLUSIONS: This is the first case of a patient presenting with acute severe UC who was treated with thalidomide, with favorable evolution. In our case the use of this drug was able to avoid the colectomy that represent the conventional but very invasive recommended therapeutic option of this condition. Therefore, thalidomide may be considered as rescue therapy in selected and carefully monitored cases of acute severe CU.

Non-alcoholic fatty liver disease and hepatocellular carcinoma in a 7-year-old obese boy: coincidence or comorbidity?

BACKGROUND: Hepatocellular carcinoma (HCC) may develop from non-alcoholic fatty liver disease (NAFLD) either in the presence or in the absence of established cirrhosis. Non-cirrhotic patients with NAFLD-related HCC are usually adult, male and obese. However, this association has not been reported yet in younger age groups. Objectives In the present study, the clinical case of a 7-yaer-old obese boy with steatosis and HCC is presented. METHODS: A 7-year-old boy, with no evidence of chronic liver disease, was admitted for assessment of a liver mass. Preliminary assessment was suggestive of a combined and severe liver steatosis together with a malignant disease. RESULTS: A biopsy confirmed the suspected diagnosis of HCC; interestingly, the non-neoplastic liver was surrounded and characterized by the presence of steatosis and ballooning, and being absent of lobular inflammation and fibrosis. Chemotherapy and diet changes were conducted successfully with ultrasound characteristics suggesting improvements on both aspects: conventional liver mass resection could take place. CONCLUSIONS: This case report suggests that HCC might develop in paediatric age patients with obesity-related NAFLD, even in the absence of fibrosis.

Diagnostic work-up of inflammatory bowel disease in children: the role of calprotectin assay.

BACKGROUND: Some reports highlight the potential application of fecal calprotectin as a direct biomarker of intestinal inflammation and, therefore, as support in choosing candidates for endoscopy. The value of 100 µg/g was recently assumed as the best cutoff for this assay. The purpose of this study was to assess the diagnostic precision of the fecal calprotectin assay, compared to histology, as a stool-screening biomarker for inflammatory bowel disease (IBD) among a group of prospectively identified patients referred for recurrent abdominal pain and altered bowel habits. METHODS: Between 1999 and 2007 we prospectively evaluated the calprotectin assay in a cohort of patients with recurrent abdominal pain and altered bowel habits associated or not with other symptoms suggestive of IBD. All patients suspected of IBD, according to Rome and Porto criteria, provided stool specimens for the calprotectin assay and subsequently underwent endoscopic procedures. RESULTS: Compared to histology, the cutoff of 100 µg/g reached a sensitivity and specificity of 100% and 68%, respectively, and a likelihood ratio (LR) of 3.1. The cutoff value of 160 µg/g, however, in our series produced the best joint estimate of sensitivity and specificity: 100% and 80%, respectively, with an LR of 5. CONCLUSIONS: In pediatric patients with recurrent abdominal pain and changes in stool habits, a positive calprotectin assay is closely associated with IBD; its systematic employment, therefore, seems to improve the process of endoscopy referral. This test, simple and inexpensive, could be included in the first noninvasive phase of an IBD diagnostic work-up.