Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

Maternal and paternal risk factors for anorectal malformations: a Dutch case-control study.

BACKGROUND: Anorectal malformations (ARM) are major congenital malformations that usually require a multitude of surgical procedures at a very early age and have a large impact on the lives of patients and their parents. The causes of ARM are still largely unknown, but they are assumed to have a multifactorial etiology. A few studies focused on environmental risk factors, but evidence is still scarce. METHODS: In this Dutch case-control study (1996-2008), we investigated the role of maternal and paternal risk factors in the etiology of ARM. Parents of 85 ARM cases and 650 controls filled in a questionnaire. Controls were children treated with ear ventilation tubes. RESULTS: A higher occurrence of fever during the first trimester of pregnancy was found for case mothers compared to control mothers (odds ratio [OR], 5.1; 95% Confidence Interval [CI], 0.9, 28.1). Maternal occupational exposure to industrial cleaning agents and solvents increased the risk of ARM three times (OR, 2.9; 95% CI, 0.9, 9.3). Overweight (Body Mass Index [BMI] > or = 25 kg/m(2)) before pregnancy also seemed to be associated with ARM (OR, 1.8; 95% CI, 1.1, 2.8), as well as maternal multivitamin use during pregnancy (OR, 1.6; 95% CI, 1.0, 2.7), paternal smoking (OR, 1.8; 95% CI, 1.1, 2.9), and paternal occupational exposure to exhaust fumes (OR, 1.9; 95% CI, 1.0, 3.6). Reported ARM in at least one first- or second-degree family member greatly increased the risk of having a child with an ARM (OR, 40.3; 95% CI, 4.8, 342.8). CONCLUSIONS: This study revealed potential risk factors for ARM, including fever during pregnancy, maternal overweight, use of multivitamins, paternal smoking, and occupational exposures, but a familial component seems important as well.

Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.

Mutations in the angiopoietin receptor TIE2/TEK have been identified as the cause for autosomal dominantly inherited cutaneomucosal venous malformation (VMCM). Thus far, two specific germline substitutions (R849W and Y897S), located in the kinase domain of TIE2, have been reported in five families. The mutations result in a fourfold increase in ligand-independent phosphorylation of the receptor. Here, we report 12 new families with TEK mutations. Although the phenotype is primarily characterized by small multifocal cutaneous vascular malformations, many affected members also have mucosal lesions. In addition, cardiac malformations are observed in some families. Six of the identified mutations are new, with three located in the tyrosine kinase domain, two in the kinase insert domain, and another in the carboxy terminal tail. The remaining six are R849W substitutions. Overexpression of the new mutants resulted in ligand-independent hyperphosphorylation of the receptor, suggesting this is a general feature of VMCM-causative TIE2 mutations. Moreover, variation in the level of activation demonstrates, to the best of our knowledge for the first time, that widely differing levels of chronic TIE2 hyperphosphorylation are tolerated in the heterozygous state, and are compatible with normal endothelial cell function except in the context of highly localized areas of lesion pathogenesis.

Minor and giant omphalocele: long-term outcomes and quality of life.

PURPOSE: Long-term outcome and quality of life in omphalocele (OC) studies are mainly focused on cosmetic disorders with the abdominal scar and gastrointestinal disorders. The aim of this study was to compare long-term mortality, morbidity, and quality of life between patients with minor and giant OCs. METHODS: Records of 89 minor and 22 giant OC children were reviewed. A questionnaire on general health was sent to all patients. A second questionnaire concerning quality of life and functional status; Darthmouth COOP Functional Health Assessment Charts/WONCA (COOP/WONCA) was sent to all patients aged 18 years or older and a peer control group. RESULTS: Of the surviving patients (69 minor OC, 20 giant OC), 12 were lost to hospital follow-up. The first questionnaire was returned by 64 (83%) of 77 patients. There were no significant differences in gastrointestinal disorders. Cosmetic problems were experienced significantly more in giant OC. The results of the COOP/WONCA charts indicated a good to very good quality of life in both groups comparable to the control group. CONCLUSIONS: Our study indicates that after a high level of medical intervention perinatally, quality of life is good to very good in both groups and comparable to healthy young adults.

Decreased mortality but increased morbidity in neonates with jejunoileal atresia; a study of 114 cases over a 34-year period.

PURPOSE: The aim of the study was to evaluate patient demographics, classification and location of the atresia, operative management, postoperative care, and outcome in 114 infants with jejunoileal atresia (JIA) over a period of more than 3 decades. METHODS: This was a retrospective case series in a tertiary care teaching hospital. Records of all patients with JIA treated at the authors' institution between 1971 and 2004 were examined. RESULTS: Sixty-two percent of atresia and stenosis was noted in the jejunum, 30% in the ileum, and 8% in both the jejunum and the ileum. Atresias and stenosis were classified as follows: 7% type 0, 16% type I, 21% type II, 24% type IIIa, 10% type IIIb, 22% type IV. Gastrointestinal anomalies were encountered in 24% of patients, genitourinary malformations in 9%, cystic fibrosis in 9%, neurologic anomalies in 6%, and congenital heart disease in 4%. Operative management included resection with primary anastomosis in 69% of all patients and temporary enterostomies in 26%. After operative management, 15% of children had resultant short bowel syndrome. Oral feeding was allowed on median day 7, and full energy expenditure via the enteric route was reached on median day 20. Forty-seven percent of infants required central venous line placement for total parenteral nutrition. Early postoperative complications occurred in 28% of patients with JIA and late postoperative complications in 17%. We observed a mortality rate of 11%. CONCLUSIONS: This is one of the largest series of neonates with JIA described. Short bowel syndrome seems to be the biggest problem resulting in longer hospital stay, more feeding problems, and higher morbidity and mortality rates. Management of children with short bowel syndrome has improved because of the use of total parenteral nutrition, new operative techniques, and better intensive care. In the last 15 years, survival has increased at the cost of the surviving children as we noted a higher percentage of late complications.

Differences between ulcerated and non-ulcerated hemangiomas, a retrospective study of 465 cases.

Our purpose was to get better insight into the ulceration of hemangiomas, by comparing patient characteristics of non-ulcerated hemangiomas with hemangiomas with active or past ulceration. A retrospective analysis was performed of files of patients who visited the Radboud University Medical Centre Nijmegen (UMCN), the Netherlands, between 1997 and 2007 for one or more infantile hemangiomas. The medical records of 465 patients were reviewed. Twenty three percent of the patients were diagnosed with ulceration. The size of ulcerated hemangiomas was significantly larger (28.6 cm2 vs. 6.0 cm2, p < 0.05). Predilection areas for ulceration were the head-neck region and the anogenital region. Ulceration was significantly most frequently seen in hemangiomas with a superficial (epidermal) component (98.5%, p < 0.05) and a segmental distribution (29.3%, p < 0.05). Ulceration most frequently took place during the proliferation phase of the hemangioma (83.1%). In the whole study population the male to female ratio was 1:2 compared to a tendency to more girls (1:3) for the group with ulcerated hemangiomas (p = 0.08). We conclude that larger, more superficial hemangiomas in areas more susceptible to trauma and contamination were more likely to ulcerate. This study contributes to the possibility of assessing the likelihood of ulceration in an individual patient.

Factors affecting quality of life of children and adolescents with anorectal malformations or Hirschsprung disease.

OBJECTIVES: First, to compare the quality of life (QL) and perceived self-competence of children and adolescents with anorectal malformations or Hirschsprung disease with that of reference groups. Second, to identify predictors of QL. PATIENTS AND METHODS: A total of 491 patients with anorectal malformations or Hirschsprung disease were sent a questionnaire, which assessed QL (mental, physical), disease-specific functioning (defecation-related), perceived self-competence (self-esteem, athletic competencies, school attitude), and demographic characteristics (sex, age). The clinical characteristics (disease severity, presence of congenital anomalies) were extracted from medical records. RESULTS: More than 50% (316, 64%) of patients with anorectal malformations or Hirschsprung disease completed the questionnaire. On average, children and adolescents in both patient groups reported no differences in QL domains compared with the reference groups. However, standard deviations revealed considerable individual variation, indicating the presence of patients with high levels of QL as well as patients with low levels of QL. Children and adolescents in both patient groups reported psychosocial problems in all domains, compared with the reference groups. Females, older patients, and those with a severe form of the disease reported lower levels of perceived self-competence and global disease-specific functioning, which in turn predicted QL. CONCLUSIONS: Our results should alert clinicians to patients who are at risk for QL problems and may therefore be in need of extra care. Our findings illustrate the importance of both global disease-specific functioning and perceived psychosocial competencies for enhancing the QL of these patients.

Pancreatic injury in children: good outcome of nonoperative treatment.

PURPOSE: Treatment of blunt injury of the pancreas in children remains controversial. Some prefer nonoperative treatment, whereas others prefer operative management in selected cases. This report reviews the treatment of patients with blunt pancreatic trauma admitted to a level I pediatric trauma center in The Netherlands. METHODS: Medical records of all children less than 15 years with blunt pancreatic trauma admitted to the University Medical Center St Radboud in the period 1975 to 2003 were retrospectively analyzed. RESULTS: Thirty-four children were included, age 3 to 14 years. Most injuries were because of bicycle accidents (58%). On admission, amylase was raised in 90% of the patients. Five patients had pancreatic duct injuries identified by imaging (endoscopic retrograde cholangiopancreaticography was used once, magnetic resonance cholangiopancreaticography twice) or at surgery. Thirty-one children were initially managed nonoperatively. Pancreatic surgery was performed in 3 children (1 Roux-Y, 2 drainage only). Mean hospital stay was 29 days in the operative group and 24 days in the nonoperative group. Fluid collections developed in 2 operated patients. Both resolved spontaneously. In 14 of the 31 nonoperated patients, a pseudocyst developed. Only 6 of these needed secondary intervention. Of these, 3 were drained percutaneously. There was no mortality and no long-term morbidity in both groups. CONCLUSIONS: Nonoperative management of pancreatic injury in children has good clinical outcome. Only 10% need secondary surgery. In 50%, pseudocysts develop of which half can be managed nonoperatively. The reliability of computed tomographic scan grading is of limited value to decide whether to operate primarily. There is little to gain with ERCP and stenting. The place of MRCP as a noninvasive diagnostic tool remains to be determined.

Genotype-phenotype correlations in MYCN-related Feingold syndrome.

Feingold syndrome (FS) is the most frequent cause of familial syndromic gastrointestinal atresia and follows autosomal dominant inheritance. FS is caused by germline mutations in or deletions of the MYCN gene. Previously, 12 different heterozygous MYCN mutations and two deletions containing multiple genes including MYCN were described. All these mutations result in haploinsufficiency of both the canonical MYCN protein and the shorter isoform, DeltaMYCN. We report 11 novel mutations including seven mutations in exon 2 that result in a premature termination codon (PTC) in the long MYCN transcript. Moreover, we have identified a PTC in exon 1 that only affects the DeltaMYCN isoform, without a phenotypic effect. This suggests that mutations in only DeltaMYCN do not contribute to the FS. Additionally, we found three novel deletions encompassing MYCN. Together with our previous report we now have a total of four missense mutations in the DNA binding domain, 19 PTCs of which six render the transcript subject to nonsense-mediated decay (NMD), and five larger deletions in a total of 77 patients. We have reviewed the clinical features of these patients, and found that digital anomalies, e.g., brachymesophalangy and toe syndactyly, are the most consistent features, present in 100% and 97% of the patients, respectively. Small head circumference was present in 89% of the cases. Gastrointestinal atresia remains the most important major congenital anomaly (55%), but cardiac and renal anomalies are also frequent. We suggest that the presence of brachymesophalangy and toe syndactyly in combination with microcephaly is enough to justify MYCN analysis.

Management of haemangiomas of infancy: a retrospective analysis and a treatment protocol.

Haemangiomas of infancy are common benign endothelial neoplasms that affect roughly 1:10 children. Treatment is indicated in complicated cases. We have evaluated treatment in a multidisciplinary setting. The charts of all affected patients between 1985 and 2000 were reviewed. The personal details, complications, indications for treatment, and outcome, were evaluated. Treatment was started in 77 of the 282 cases reviewed. Ulceration and bleeding were the most common complications and were successfully treated when indicated in 29/39 patients (74%) with wound dressings and antibiotics. Systemic steroids were given to 18 patients, usually for block of the visual fields and respiratory impairment. A good or moderate result was obtained in 16/18 patients. Twelve patients required operation. Based on our results and those of others, we propose a protocol for treatment.

Closure of giant omphaloceles by the abdominal wall component separation technique in infants.

BACKGROUND/PURPOSE: Several techniques have been described to repair giant omphaloceles. There is no procedure considered to be the criterion standard worldwide. The aim of the present prospective study was to analyze the early and late results of secondary closure of giant omphaloceles using the component separation technique (CST) in infants. METHODS: From January 2004 to January 2007, 10 consecutive pediatric patients with a giant omphalocele were treated at our department. Initially, patients were treated conservatively. After epithelialization of the omphalocele, the abdominal wall was reconstructed using CST. Patients were monitored for complications during admission, and all patients were seen for follow-up. RESULTS: Component separation technique was performed at median age of 6.5 months (range, 5-69 months). The median diameter of the hernia was 8 cm (range, 6-9 cm). There was no mortality. The postoperative course was uneventful in 7 patients. Complications were seen in 3 patients (infection, skin necrosis, and hematoma). Median hospital stay was 7 days. After median follow-up of 23.5 months (range, 3-39 month), no reherniations were found. CONCLUSIONS: The CST is a safe 1-stage procedure for secondary closure in children with a giant omphalocele without the need for prosthetic material and with good clinical outcome.

Severe mental retardation, epilepsy, anal anomalies, and distal phalangeal hypoplasia in siblings.

We report two sisters born to consanguineous parents with an identical syndrome consisting of severe mental retardation and epilepsy, hypoplastic terminal phalanges, and anteriorly displaced anus. Further metabolic and genetic testing failed to detect the etiology. A whole genome linkage scan showed homozygosity for a 28-Mb region on chromosome 1p, and a 65-Mb region spanning most of chromosome 14. These results are consistent with an autosomal recessive condition that is similar to, but likely distinct from, Coffin-Siris syndrome.

Explaining change in quality of life of children and adolescents with anorectal malformations or Hirschsprung disease.

OBJECTIVES: The purpose of this work was to examine changes in quality of life, disease-specific functioning, and psychosocial competencies of children and adolescents (8-16 years of age) with anorectal malformations or Hirschsprung disease and to identify predictors of change in quality of life by testing an explanatory model in which background variables explained changes in quality of life via changes in disease-specific functioning and psychosocial competencies. METHODS: Questionnaires were administered to 129 patients with anorectal malformations and 121 patients with Hirschsprung disease within a 3-year interval. Clinical and sociodemographic background variables were measured on the first occasion. Quality of life (physical and mental), disease-specific functioning (defecation-related), and psychosocial competencies (self-esteem, athletic competencies, and school attitude) were measured on both occasions. RESULTS: Patients improved in disease-specific functioning and mental quality of life. Changes in quality of life were indeed explained by the explanatory model. Among other things, the results indicated that patients with a severe form of the disease or with additional congenital diseases showed worsening of school attitude, which in turn affected change in mental quality of life negatively. CONCLUSIONS: Children and adolescents with anorectal malformations or Hirschsprung disease reported better quality of life over time. To improve and maintain an optimal level of children's and adolescents' quality of life, it is important to direct treatment both to reducing symptoms and enhancing psychosocial competencies, in particular by paying attention to school attitude.

Hirschsprung's disease: healthcare meets the needs.

OBJECTIVE: The objective of this study was to examine the types of healthcare services used by children, adolescents, and adults with Hirschsprung Disease (HD) in relation to the severity of the initial defect (mild, severe), whether additional care was needed, the provision of information, transfer to adult care, and satisfaction with the care provided. METHODS: Three hundred twenty (71%) HD patients, ages 6 to 54, completed a questionnaire that assessed the use of healthcare services, the need for more healthcare, the provision of information, the transfer to adult care and satisfaction with the provided care. RESULTS: In 6 months, 45% of the children, 14% of the adolescents, and 15% of the adults consulted a medical specialist. Compared with patients with a mild form of HD in the age range of 6 to 16 years, only the more severely afflicted adult patients visited medical professionals more often (10% vs 29%) (P < .05). Of the children, the adolescents, and the adults 23%, 8%, and 6% respectively consulted a nonmedical professional. Less than 15% of all patients whould have liked more treatment. In 6 months 51% of the children, 24% of the adolescents, and 21% of the adults received treatment information, of which respectively 14, 8, and 20% wished they had received more information. Three (12%) patients who needed adult care encountered problems with the transfer. Almost all patients were satisfied with the care provided. CONCLUSIONS: There is good access to medical healthcare services, especially for children. The only lacuna in the healthcare system we revealed was a lack of information, particularly for adult patients. Most parents and patients reported to be very satisfied with the provided care.

The pathogenesis of hemangiomas: a review.

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Differentiate between hemangiomas and vascular malformations. 2. Describe arguments for the trophoblast origin of hemangiomas. 3. Give arguments for the angioblast theory for the origin of hemangiomas. 4. Identify key genes involved in the origin of hemangiomas. BACKGROUND: Hemangiomas of infancy are common endothelial tumors. They differ from vascular malformations in their tissue architecture and biological properties. To date, there is no universally accepted theory that explains the pathogenesis and pathophysiology of hemangiomas. METHODS: Theories from the medical literature from 1981 to 2004 were gathered, categorized, and reviewed. RESULTS: Current research is mostly on the cellular and genetic levels. The most authoritative theories focus on angioblast origins, trophoblast origins, mutations in cytokine regulatory pathways, and field defects as the cause of the deranged angiogenesis of hemangiomas. CONCLUSIONS: To date, no single theory can easily explain all the characteristics of hemangiomas, such as predilection for the female sex, usual occurrence after birth, spontaneous involution, abnormal tissue architecture, and distribution within a developmental field. Hemangiomas are probably the final common expression of several pathophysiological mechanisms taking effect alone or in combination.

Explaining change over time in quality of life of adult patients with anorectal malformations or Hirschsprung's disease.

PURPOSE: The aim of this study was to examine changes in the quality of life of adult patients with anorectal malformations or Hirschsprung's disease over a three-year interval and to identify demographic, clinical, and psychosocial variables that explain possible quality-of-life changes. Understanding the factors that affect changes in quality of life over time is particularly important to provide adequate care. METHODS: Questionnaires were administered to 261 patients (77 percent), with a three-year interval. Background characteristics, including demographic and clinical variables, and psychosocial variables (i.e., self-esteem, mastery, social support, disease cognition) were measured on one occasion. Generic and disease-specific quality of life were measured twice. RESULTS: On average patients indicated no change in quality-of-life level after three years. However, variance in the change scores revealed individual variation, indicating the presence of patients who improved and patients who deteriorated. Patients who were female, older, have other congenital diseases, or a stoma reported poorer quality of life over time. The psychosocial variable "disease cognition" most strongly affected the change in quality of life of patients with anorectal malformations or Hirschsprung's disease. CONCLUSIONS: Our results could alert clinicians to patients who are at risk for quality-of-life deterioration and might therefore be in need for extra care. Our findings illustrate the importance of psychosocial functioning for enhancing the quality of life over time of these patients.

Allergic colitis presenting within the first hours of premature life.

UNLABELLED: A prematurely born infant developed rectal blood loss several hours after birth, after his first formula feeding. Discontinuing the feeding resolved symptoms, but after resuming feeding rectal blood loss reappeared. There were no signs of necrotizing enterocolitis. Suspecting cow's milk allergy, the feeding was changed to a casein-based protein hydrolysate, without effect. Meanwhile, laboratory tests indicated cow's milk allergy. Symptoms only resolved after introducing an amino acid-based formula supporting a definite diagnosis of cow's milk-induced allergic colitis. This is the first description of a premature infant with symptoms of allergic colitis, appearing within hours after birth, suggestive of intrauterine sensitization. The exact mechanisms of sensitization remain obscure. CONCLUSION: Cow's milk-induced allergic colitis can occur after the first feed, even in a prematurely born neonate. This is most probably due to intrauterine sensitization, and should be included in the differential diagnosis of rectal blood loss.

Anorectal malformations: does healthcare meet the needs?

OBJECTIVES: The first aim was to identify the types of healthcare services used by children, adolescents, and adults with anorectal malformation (ARM) in relation to the severity of their disease and to examine whether additional care was needed. The second aim was to evaluate specific areas in the healthcare system, including provided information, transfer from pediatric to adult care, and satisfaction with the provided care. METHODS: Three hundred eighty-six (61%) patients with ARM, ages 6 to 52, completed a questionnaire that assessed their use of healthcare services and the need for additional services. Also, questions were asked about specific areas in the healthcare system. Clinical and sociodemographic characteristics were extracted from medical records. RESULTS: In the preceding 6 months 50% of the children, 24% of the adolescents, and 24% of the adults consulted a medical specialist. Compared with patients with a mild form of ARM in the age range of 6 to 16 years, the more severely afflicted patients visited medical professionals more often (18% vs. 32%). Particularly, adolescents in the age range of 12 to 16 years with a severe form of the disease more often visited the pediatric surgeon than their peers with a mild form (2% vs. 16%). Twenty-three percent of the children, 7% of the adolescents, and 8% of the adults consulted a nonmedical professional. Twenty percent of the children, 13% of the adolescents, and 17% of the adults would have liked additional or more treatment of a nonmedical professional. In 6 months, 40% of the children, 24% of the adolescents, and 20% of the adults received treatment information. One third of the adult patients who were transferred to "adult" surgeons encountered transfer problems. Almost all patients were satisfied with the care provided. CONCLUSIONS: There is good access to medical healthcare services, especially for children. However, more psychosocial and paramedical care is considered necessary. As could be expected, children and adolescents with a severe form of the disease reported to have visited a medical specialist more often. Although healthcare for patients with ARM may be improved at certain points, most parents and patients were very satisfied with the care provided.

MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.

Feingold syndrome is characterized by variable combinations of esophageal and duodenal atresias, microcephaly, learning disability, syndactyly and cardiac defect. We show here that heterozygous mutations in the gene MYCN are present in Feingold syndrome. All mutations are predicted to disrupt both the full-length protein and a new shortened MYCN isoform, suggesting that multiple aspects of early embryogenesis and postnatal brain growth in humans are tightly regulated by MYCN dosage.