SDF-1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception.

The precise mechanisms of SDF-1 (CXCL12) in angiogenesis are not fully elucidated. Recently, we showed that Notch inhibition induces extensive intussusceptive angiogenesis by recruitment of mononuclear cells and it was associated with increased levels of SDF-1 and CXCR4. In the current study, we demonstrated SDF-1 expression in liver sinusoidal vessels of Notch1 knockout mice with regenerative hyperplasia by means of intussusception, but we did not detect any SDF-1 expression in wild-type mice with normal liver vessel structure. In addition, pharmacological inhibition of SDF-1/CXCR4 signalling by AMD3100 perturbs intussusceptive vascular growth and abolishes mononuclear cell recruitment in the chicken area vasculosa. In contrast, treatment with recombinant SDF-1 protein increased microvascular density by 34% through augmentation of pillar number compared to controls. The number of extravasating mononuclear cells was four times higher after SDF-1 application and two times less after blocking this pathway. Bone marrow-derived mononuclear cells (BMDC) were recruited to vessels in response to elevated expression of SDF-1 in endothelial cells. They participated in formation and stabilization of pillars. The current study is the first report to implicate SDF-1/CXCR4 signalling in intussusceptive angiogenesis and further highlights the stabilizing role of BMDC in the formation of pillars during vascular remodelling.

A Case of Congenital Infantile Fibrosarcoma of the Bowel Presenting as a Neonatal Intussusception.

Neonatal intussusception of the intestinal tract is rare. However, most neonatal intussusceptions have an organic lead point. For the lead point to be a neoplasm is extremely rare. We report a case that presented with neonatal intussusception with a congenital infantile fibrosarcoma as the lead point. The detection of ETV6-NTRK3 gene fusion was useful, although the definitive diagnosis was achieved by a comprehensive evaluation including this gene analysis, standard histology and immunohistochemistry. Neonatal intussusception should be suspected to be caused by a neoplasm. If pathological diagnosis is difficult, molecular analysis should be utilized to diagnose congenital infantile fibrosarcoma.

Brain angioarchitecture and intussusceptive microvascular growth in a murine model of Krabbe disease.

Defects of the angiogenic process occur in the brain of twitcher mouse, an authentic model of human Krabbe disease caused by genetic deficiency of lysosomal ß-galactosylceramidase (GALC), leading to lethal neurological dysfunctions and accumulation of neurotoxic psychosine in the central nervous system. Here, quantitative computational analysis was used to explore the alterations of brain angioarchitecture in twitcher mice. To this aim, customized ImageJ routines were used to assess calibers, amounts, lengths and spatial dispersion of CD31(+) vessels in 3D volumes from the postnatal frontal cortex of twitcher animals. The results showed a decrease in CD31 immunoreactivity in twitcher brain with a marked reduction in total vessel lengths coupled with increased vessel fragmentation. No significant changes were instead observed for the spatial dispersion of brain vessels throughout volumes or in vascular calibers. Notably, no CD31(+) vessel changes were detected in twitcher kidneys in which psychosine accumulates at very low levels, thus confirming the specificity of the effect. Microvascular corrosion casting followed by scanning electron microscopy morphometry confirmed the presence of significant alterations of the functional angioarchitecture of the brain cortex of twitcher mice with reduction in microvascular density, vascular branch remodeling and intussusceptive angiogenesis. Intussusceptive microvascular growth, confirmed by histological analysis, was paralleled by alterations of the expression of intussusception-related genes in twitcher brain. Our data support the hypothesis that a marked decrease in vascular development concurs to the onset of neuropathological lesions in twitcher brain and suggest that neuroinflammation-driven intussusceptive responses may represent an attempt to compensate impaired sprouting angiogenesis.

Severe acute abdomen caused by symptomatic Meckel's diverticulum in three children with trisomy 18.

Meckel's diverticulum (MD) is the most prevalent congenital anomaly of the gastrointestinal tract and often presents a diagnostic challenge. Patients with trisomy 18 frequently have MD, but the poor prognosis and lack of consensus regarding management for neonates has meant that precise information on the clinical manifestations in infants and children with MD is lacking. We describe the cases of three children with trisomy 18 who developed symptomatic MD. Intussusception was diagnosed in Patient 1, intestinal volvulus in Patient 2, and gastrointestinal bleeding in Patient 3. All three patients underwent surgical treatment and only the Patient 1 died due to pulmonary hypertensive crisis. The other two patients experienced no further episodes of abdominal symptoms. In patients with trisomy 18, although consideration of postoperative complications and prognosis after surgical treatment is necessary, symptomatic MD should carry a high index of suspicion in patients presenting with acute abdomen.

MIRAGE Syndrome Caused by a De Novo c.3406G>C (p. Glu1136Gln) Mutation in the SAMD9 Gene Presenting With Neonatal Adrenal Insufficiency and Recurrent Intussusception: A Case Report.

Introduction: Primary adrenal insufficiency (PAI) presenting in the neonatal period can be life threatening and requires early recognition, diagnosis, and management. PAI due to adrenal hypoplasia (syndromic/non-syndromic) is a rare disorder. MIRAGE is a recently described syndrome with PAI and multisystem involvement. Case Presentation: A preterm female neonate presenting with PAI and persistent severe thrombocytopenia was diagnosed to have MIRAGE syndrome due to a de novo pathogenic variant c.3406G>C (p. Glu1136Gln) in the SAMD9 gene. In the first year of life, she had recurrent respiratory and gastrointestinal infection causing failure to thrive. At 17 months, she suffered recurrent intussusception requiring treatment with parenteral nutrition and high-dose steroids. Subsequently, she established oral feeds with hydrolysed formula and demonstrated good weight gain. Conclusion: In neonates presenting with PAI and associated multisystem involvement, a thoughtful approach and genetic testing is valuable in discerning an etiological diagnosis. This case of MIRAGE adds to the spectrum of reported cases and is the first to report on recurrent intussusception and its management with high-dose steroids.

STK11 status and intussusception risk in Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by germline STK11 mutations and characterised by gastrointestinal polyposis. Although small bowel intussusception is a recognised complication of PJS, risk varies between patients. OBJECTIVE: To analyse the time to onset of intussusception in a large series of PJS probands. METHODS: STK11 mutation status was evaluated in 225 PJS probands and medical histories of the patients reviewed. RESULTS: 135 (60%) of the probands possessed a germline STK11 mutation; 109 (48%) probands had a history of intussusception at a median age of 15.0 years but with wide variability (range 3.7 to 45.4 years). Median time to onset of intussusception was not significantly different between those with identified mutations and those with no mutation detected, at 14.7 years and 16.4 years, respectively (log-rank test of difference, chi(2) = 0.58, with 1df; p = 0.45). Similarly no differences were observed between patient groups on the basis of the type or site of STK11 mutation. CONCLUSIONS: The risk of intussusception in PJS is not influenced by STK11 mutation status.

Meckel's diverticulum induced intrauterine intussusception associated with ileal atresia complicated by meconium peritonitis.

Intrauterine intussusception with a leading point of Meckel's diverticulum is a rare cause of ileal atresia, which may cause bowel obstruction and perforation. We report such a case complicated by meconium peritonitis. The fetal ultrasonogram revealed ascites, dilated bowel loops and intra-abdominal calcification at a gestational age of 30 weeks. The patient was delivered at 37 weeks and laparotomy was performed to manage the intestinal obstruction. The operative findings showed that Meckel's diverticulum had induced intussusception associated with the ileal atresia with meconium peritonitis. The ileum was resected with end-to-end anastomosis. The postoperative course was uneventful. In this patient, ascites and intraperitoneal calcification were caused by ileal atresia, which may have been induced by intrauterine intussusception.

[A colo-colic invagination on the basis of MutYH-associated polyposis in a boy aged 14]. / Een colocolische invaginatie op basis van MutYH-geassocieerde polyposis coli bij een jongen van 14 jaar.

A 14-year-old boy presented with acute abdominal pain, vomiting and diarrhoea. Colo-colic intussusception was diagnosed by means of a colonic contrast X-ray. The intussusception was successfully reduced during this procedure. Hundreds of polyps were seen throughout the entire colon. Genetic research showed a mutation of the MutYH gene. Proctocolectomy with ileoanal pouch anastomosis was carried out. The pathology specimen showed an intramucosal carcinoma and multiple adenomas. MutYH-associated polyposis coli is an autosomal recessive disease that occurs as a result of a mutation in the MutYH gene. This will lead to polyposis coli. An intussusception is a rarely seen symptom. Patients need preventive surgical treatment because of the high risk developing a colorectal carcinoma.

Endoglin inhibition leads to intussusceptive angiogenesis via activation of factors related to COUP-TFII signaling pathway.

Angiogenesis is a highly coordinated, extremely complex process orchestrated by multiple signaling molecules and blood flow conditions. While sprouting mode of angiogenesis is very well investigated, the molecular mechanisms underlying intussusception, the second mode of angiogenesis, remain largely unclear. In the current study two molecules involved in vascular growth and differentiation, namely endoglin (ENG/CD105) and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) were examined to unravel their specific roles in angiogenesis. Down- respectively up-regulation of both molecules tightly correlates with intussusceptive microvascular growth. Upon ENG inhibition in chicken embryo model, formation of irregular capillary meshwork accompanied by increased expression of COUP-TFII could be observed. This dynamic expression pattern of ENG and COUP-TFII during vascular development and remodeling correlated with formation of pillars and progression of intussusceptive angiogenesis. Similar findings could be observed in mammalian model of acute rat Thy1.1 glomerulonephritis, which was induced by intravenous injection of anti-Thy1 antibody and has shown upregulation of COUP-TFII in initial phase of intussusception, while ENG expression was not disturbed compared to the controls but decreased over the time of pillar formation. In this study, we have shown that ENG inhibition and at the same time up-regulation of COUP-TFII expression promotes intussusceptive angiogenesis.

Peutz-Jeghers syndrome: early clinical expression of a new STK11 gene variant.

Genetic heterogeneity has been recognised in Peutz-Jeghers syndrome (PJS) (over 230 STK11 gene mutations reported). We report a rare PJS phenotype with early extensive gastrointestinal (GI) presentation and a new genetic variant. The case presented as haematochezia and mucocutaneous pigmentation (the patient was 3 years of age). Endoscopy showed several polyps throughout the stomach/colon (PJ-type hamartomas); the larger polyps were resected. Small bowel imaging detected multiple jejunum/ileum small polyps. During 8 years of follow-up of this asymptomatic patient, an increasing number of diffusely distributed polyps was observed and polypectomies were performed. Subsequently, the patient failed consultations; when the patient was 13 years of age, emergency surgery was required due to small bowel intussusception (ileal polyp). A STK11 gene study identified two missense variants in heterozygous (yet unknown significance but probably pathogenic): c.854T>A (exon 6) and c.446C>T* (exon 2) (*not previously reported). We report two STK11 gene variants (one not previously described) of yet undetermined causality in a paediatric patient presenting with extensive GI involvement at a very early age, with no family medical history. Structural and functional repercussion of the newly described variants should be further investigated.

Familial intussusception.

We report a father and two sons who each suffered from recurrent acute ileocolic intussusception in childhood, suggesting that there may in some cases be a genetic predisposition to the condition. This might have an anatomical basis.

Familial idiopathic intussusception: a report of two families.

The authors report on two families with 5 out of 10 and two of two siblings who presented with idiopathic ileocolic intussusception. This may suggest hereditary predisposition as an etiologic factor.

Peutz-Jeghers syndrome in children: report of two cases and review of the literature.

In this article, we report two new cases of Peutz-Jeghers syndrome in children and review the literature over the past twenty years. This series of 70 cases demonstrates that the clinical pictures observed in children are similar to those of adults. Rectal prolapse or extrusion of polyps can be the clue to the diagnosis at an early age, even in the absence of pigmentation, which can appear later. Gastroduodenal polyps were strikingly frequent in the less than or equal to 16-yr-old group (62%) a circumstance that can create operative difficulties. Five out of the 70 patients (7.14%) had tumors during childhood (two gastrointestinal adenocarcinomas, two ovarian and one testicular neoplasms). A higher risk of tumor development in these patients does exist either as a result of degeneration of the polyps or of a genetic predisposition. Whenever operation becomes necessary, a very cautious approach must be advised in order to preserve as much intestinal length as possible in these patients, who have a lifelong disease which may require repeated operations.

The usefulness of intra-operative endoscopy in Peutz-Jeghers syndrome: a case report.

The Peutz-Jeghers syndrome is an autosomal dominant inherited disease manifested by a combination of mucocutaneous pigmentation and gastrointestinal hamartomatous polyps that usually cause intussusception and intestinal hemorrhage. We report a case in which the patient has been followed-up on for 14 years and who underwent surgical and endoscopic polyp removal several times as well as one intestinal resection. This time, with the use of combined surgery and perioperative endoscopy, 27 polyps were removed, performing only 3 enterotomies. This is the highest number in one session to be reported in the literature. The usefulness of this technique is providing a "clean small intestine" that allows the patient a longer time interval between laparotomies and reduces the complications associated with multiple laparotomies and resections.

Familial intussusception: report of a case with recurrence in the youngest sibling and review of the literature.

The etiology of idiopathic intussusception is unknown. Occurrence of intussusception in more than one patient in a same family is rare. A familial predisposition is suspected. We present a family in which the two children suffered from intussusception with recurrence in the youngest sibling and review the literature.