Assessment and outcome of children with intestinal failure referred for intestinal transplantation.

BACKGROUND & AIMS: Chronic intestinal failure (CIF) requires long term parenteral nutrition (PN) and, in some patients, intestinal transplantation (ITx). Indications and timing for ITx remain poorly defined. In the present study we aimed to analyze causes and outcome of children with CIF. METHODS: 118 consecutive patients referred to our institution were assessed by a multidisciplinary team and four different categories were defined retrospectively based on their clinical course: Group 1: patients with reversible intestinal failure; group 2: patients unsuitable for ITx, group 3: patients listed for ITx; group 4: patients stable under PN. Analysis involved comparison between groups for nutritional status, central venous catheter (CVC) related complications, liver disease, and outcome after transplantation by using non parametric tests, Mann-Whitney tests, Kruskal-Wallis, Wilcoxon signed rank tests and chi square distribution for percentage. RESULTS: 118 children (72 boys) with a median age of 15 months at referral (2 months-16 years) were assessed. Etiology of IF was short bowel syndrome [n = 47], intractable diarrhea of infancy [n = 37], total intestinal aganglionosis [n = 18], and chronic intestinal pseudoobstruction [n = 17]. Most patients (89.8%) were totally PN dependent, with 48 children (40.7%) on home-PN prior to admission. Nutritional status was poor with a median body weight at -1.5 z-score (ranges: -5 to +2.5) and median length at -2.0 z-score (ranges: -5.5 to +2.3). The mean number of CVC inserted per patient was 5.2 (range 1-20) and the mean number of CRS per patient was 5.5 (median: 5; range 0-12) Fifty-five patients (46.6%) had thrombosis of ≥2 main venous axis. At admission 34.7% of patients had elevated bilirubin (≥50 µmol/l), and 19.5% had platelets <100,000/ml, and 15% had both. Liver biopsy performed in 79 children was normal (n = 4), or showed F1 or F2 fibrosis (n = 29), bridging fibrosis F3 (n = 20), or cirrhosis (n = 26). Group 1 included 10 children finally weaned from PN (7-years survival: 100%). Group 2 included 12 children with severe liver disease and associated disorders unsuitable for transplantation (7-years survival: 16.6%). Group 3 included 66 patients (56%) who were listed for small bowel or liver-small bowel transplantation, 62/66 have been transplanted (7 years survival: 74.6%). Factors influencing outcome after liver-ITx were body weight (p < .004), length (p < .001), pre-Tx bilirubin plasma level (p < .001) and thrombosis (p < .01) for isolated ITx, Group 4 included 30 children (25.4%) with irreversible IF considered as potential candidates for isolated ITx. Four children were lost from follow up and 3 died within 2 years (survival 88.5%). Among potential candidates, the following parameters improved significantly during the first 12 months of follow up: Body weight (p.0001), length (p < .0001) and bilirubin (p < .0001). CONCLUSIONS: many patients had a poor nutritional status with severe complications especially liver disease. PN related complications were the most relevant indication for ITx, but also a negative predictor for outcome. Early patient referral for Tx-assessment might help to identify and separate children with irreversible IF from children with transient IF or uncomplicated long-term PN, allowing to adapt a patient-based treatment strategy including or not ITx.

[Enigmatic lymphatic diseases involving the lung]. / Pathologies énigmatiques des lymphatiques comportant une atteinte pulmonaire.

Lymphedema associated with other developmental malformations (Milroy syndrome, Hennekam syndrome, Noonan syndrome, Gorham-Stout syndrome, yellow nail syndrome) are unfrequent disease, but explorations led to the identification of genetic mutations that have then been validated in mouse models. However, lymphatic vessels complexity and its proximity with the venous system suggest the need for further researches, especially in the comprehension of pulmonary symptoms.

[Congenital lung malformations--when to operate?]. / Malformations congénitales du poumon: quand opérer ?

Advances in antenatal imaging over the past 10 years have completely changed diagnosis and management of congenital lung disease, especially for congenital cystic adenomatoid malformations and sequestrations that are the two lesions most commonly detected. If early surgical excision is required for symptomatic cases, management of asymptomatic malformations is still discussed. The natural evolution and consequences of later complications of congenital lung malformations need to be compared with the benefits of elective resection and surgical morbidity. Complete regression of sequestrations or clinical and morphological improvement in congenital lobar emphysema pleads for clinical watching. On the other hand, resection is advocated for cystic malformations, because of an increased risk of acute respiratory distress, later infections and the possibility of malignant transformation. Even though the proportion of asymptomatic patients that go on to develop symptoms is hard to evaluate, an argument for elective surgery is a better outcome than emergency surgery. Further studies and long term follow-up are still needed to understand the natural history of congenital lung malformations precisely and help to define the optimal way in which to manage them.

[When congenital lung malformations have to be operated?]. / Quand les malformations pulmonaires congénitales doivent-elles être opérées ?

Both technical and anatomical features and the need for a long follow-up, usually over several years, explain the specificity of lung surgery in children. Apart from the oncological resections, the main indications for this surgery are congenital lung anomalies (cystic adenomatoid malformation, bronchopulmonary sequestration, lobar emphysema), symptomatic postinfectious lesions (bronchiectasis, atelectasis, abscess) and pneumothorax. Advances in miniaturization of the surgical equipment are used to carry the majority of these interventions by thoracoscopy, except when performed at the neonatal period. In the newborn, for which the indications for lung surgical resections are exceptional, ventilatory conditions and the tightness of the chest lead to still prefer open surgery. Pulmonary malformations can also be managed prenatally when they affect lung development or cause heart failure because of compressive complications. These interventions, performed after the 30th week of gestation, are not intended to remove the lesions, but to release the compression. But these procedures are still under evaluation and, in light of possible fetal and maternal complications, they should only be performed in tertiary centers and in the context of specific protocols.

Factors associated with partial and complete regression of fetal lung lesions.

OBJECTIVE: A decrease in the volume of congenital pulmonary malformations (CPM) can be observed on prenatal ultrasonography, but the underlying mechanism for this phenomenon is unknown. Our objective was to identify factors associated with the prenatal reduction in size of cystic and/or hyperechoic lung lesions. METHODS: This was a retrospective study of cases with a prenatal diagnosis of hyperechoic and/or cystic lung lesion. The extent of reduction in lesion size was calculated from ultrasound measurements. Clinical, ultrasound, radiological and histological data were tested for their relationship with prenatal CPM reduction. RESULTS: In a 4-year period, 36 patients were referred with a cystic and/or hyperechoic fetal lung lesion diagnosed at a mean gestational age of 23.4 weeks. The lesions were cystic in 16 cases (44%), hyperechoic in 12 (33%) and both in eight (22%). The malformation was no longer visible before birth (apparent disappearance) in nine cases (25%), shrank by 18-90% in 15 (42%) and did not reduce in 12 (33%). Findings on postnatal computed tomography were always abnormal. Isolated hyperechoic lesions were significantly more likely to shrink in utero. The mean reductions were 79%, 35% and 19%, for isolated hyperechoic, cystic and mixed lesions, respectively (P=0.001). Only 8% of hyperechoic lesions demonstrated no volume reduction, as compared to 50% and 42% of cystic and mixed lesions, respectively (P=0.03). Greater gestational age at birth was also associated with a decrease in the incidence of malformations (P=0.02). In cases that underwent surgery, hyperechoic lesions were linked to a variety of pathological diagnoses, whereas cystic lesions were all described histologically as congenital cystic adenomatoid malformations. CONCLUSIONS: Prenatal size reduction of fetal lung malformations is associated with isolated hyperechogenicity and greater gestational age at birth. This might result from the resumption of normal lung development after local disruption of lung growth.

[Recurrent and metastatic infantile fibrosarcoma: a case report]. / Fibrosarcome infantile récidivant et métastatique: à propos d'un cas.

Infantile fibrosarcoma is a rare malignant tumor that usually occurs during the 1st year of life. It accounts for approximately 5-10% of all sarcomas in infants younger than 1 year of age. It usually has indolent progression and metastatic spread is rare. We report the case of a patient who had infantile fibrosarcoma of the trunk. At birth, the baby presented a soft tissue mass of the scapulothoracic region. Histopathological examination after complete surgical resection at first suggested an angioma. Reanalysis of the histology after a metastatic relapse resulted in the diagnosis of infantile fibrosarcoma, which was confirmed by the presence of the specific translocation seen in infantile fibrosarcoma (ETV6/NTRK3). This patient's progression was uncommon because he developed 3 metastatic relapses. The treatment consisted of surgery, chemotherapy, and radiation therapy. The patient is alive with persistent complete remission. We discuss the diagnostic and therapeutic issues of infantile fibrosarcoma. There is a risk of erroneous diagnosis in newborn infants between benign angiomatous tumor and infantile fibrosarcoma. The fusion transcript ETV6-NTRK3 resulting from the specific chromosomal translocation t(12;15)(p13;q25) is now a useful diagnostic tool for infantile fibrosarcoma. Surgery with wide resection is the mainstay of treatment. However, infantile fibrosarcoma is a chemosensitive tumor. If initial surgery cannot be done without mutilation or is impossible, preoperative chemotherapy should be given. The role of radiation therapy is still debated.

Transfer of surgical competences in the treatment of intersex disorders in Togo.

BACKGROUND: To evaluate the impact of scientific seminar on the sexual ambiguity on patients and paediatric surgeons in French-speaking African countries. MATERIALS AND METHODS: This was a report of the proceeding of a teaching seminar on intersex management, which was held from December 4 th to 8 th , 2006, in the Paediatric Surgery Department of Tokoin Teaching Hospital and the Surgery Department of "Saint Jean de Dieu" Hospital of Afagnan, Togo. RESULTS: There were 107 participants [five professors of paediatric surgery, 62 African paediatric surgeons (including 15 from African French-speaking countries), and 40 general surgeons]. The workshop involved a two-day theoretical teaching session (aimed at understanding, recognising, and treating the sexual ambiguities), and practical session; during these sessions different intersexes (one case of mixed gonadal dysgenesis, two of female pseudohermaphroditism, and two of male pseudohermaphroditism), were operated free of charge. Participants expressed satisfaction and confidence with regard to the management of intersex after the seminar. CONCLUSION: This scientific forum allowed possible exchange of competence among the paediatric surgeons with regard to efficient treatment of sexual ambiguities.

Transfer of surgical competences in the treatment of intersex disorders in Togo

Background: To evaluate the impact of scientific seminar on the sexual ambiguity on patients and paediatric surgeons in French-speaking African countries. Materials and Methods: This was a report of the proceeding of a teaching seminar on intersex management; which was held from December 4 th to 8 th ; 2006; in the Paediatric Surgery Department of Tokoin Teaching Hospital and the Surgery Department of ""Saint Jean de Dieu"" Hospital of Afagnan; Togo. Results: There were 107 participants [five professors of paediatric surgery; 62 African paediatric surgeons (including 15 from African French- speaking countries); and 40 general surgeons]. The workshop involved a two-day theoretical teaching session (aimed at understanding; recognising; and treating the sexual ambiguities); and practical session; during these sessions different intersexes (one case of mixed gonadal dysgenesis; two of female pseudohermaphroditism; and two of male pseudohermaphroditism); were operated free of charge. Participants expressed satisfaction and confidence with regard to the management of intersex after the seminar. Conclusion: This scientific forum allowed possible exchange of competence among the paediatric surgeons with regard to efficient treatment of sexual ambiguities"

Is intestinal transplantation the future of children with definitive intestinal insufficiency?

UNLABELLED: Intestinal transplantation (IT) is the newest and most difficult of organ transplantations. The first ever (1987) and the longest surviving (1989) IT were performed in our institution. However, IT still has to demonstrate its benefit to children on long-term parenteral nutrition (PN). We tried to clarify this aspect by looking back at our 13 years' experience. PATIENTS: From 1994 to December 2007, 74 IT were performed in 69 children, 39 with an isolated small bowel (IT), 35 combined with a liver transplant (LITx). The indications were: short bowel syndrome (n = 25), congenital mucosal diseases (n = 22), and motility disorders (n = 22). Median age at transplantation was 5 years (1 - 17 years). Follow-up was 1 to 12 years (median 5 years). RESULTS: Thirty-one children have a functioning graft (42 %), 15/39 IT, 16/35 LITx. They are at home without PN, with a good quality of life. One child is PN-dependent 1.5 years post IT. Post IT, 16 children were detransplanted: 12 early on (1 for mechanical complications, 11 because of resistant rejection; 3 less than 3 years, one 9 years post SBT (chronic rejection). In 2 noncompliant teenagers, PN was reintroduced (one was detransplanted later on). Several years post LITx, 2 children underwent bowel detransplantation due to an acute viral infection complicated with rejection. Twenty-two children died (32 %, 8 IT, 14 LITx), 18 early on from infectious or surgical complications, 4 more than 1 year post IT, 3 after retransplantation (1 in another unit). Bad prognostic factors are multiple previous surgeries, an older age (> 7 y), and chronic intestinal pseudo-obstruction. DISCUSSION: Complications post IT are frequent and life-threatening, especially early on: rejection (IT), infections (LITx). Later on, the rate of complications decreases but remains significant, especially in noncompliant patients. However we describe here a 13-year learning curve; the recent results are encouraging with regard to control of rejection and viral infections. CONCLUSION: Intestinal transplantation is indicated only in selected patients in whom long-term PN cannot be performed safely any more. In every child with intestinal insufficiency, the therapeutic strategy must be discussed early on in order to perform IT at the right time under optimal conditions. IT should evolve from being a "rescue" procedure to becoming a true therapeutic option.

Spectrum of HLXB9 gene mutations in Currarino syndrome and genotype-phenotype correlation.

Currarino syndrome (CS) is a rare congenital malformation described in 1981 as the association of three main features: typical sacral malformation (sickle-shaped sacrum or total sacral agenesis below S2), hindgut anomaly, and presacral tumor. In addition to the triad, tethered cord and/or lipoma of the conus are also frequent and must be sought, as they may lead to severe complications if not treated. The HLXB9 gene, located at 7q36, is disease-causing. It encodes the HB9 transcription factor and interacts with DNA through a highly evolutionarily conserved homeodomain early in embryological development. Thus far, 43 different heterozygous mutations have been reported in patients fulfilling CS criteria. Mutation detection rate is about 50%, and reaches 90% in familial cases. Here, we report 23 novel mutations in 26 patients among a series of 50 index cases with CS, and review mutational reports published since the identification of the causative gene. Three cytogenetic anomalies encompassing the HLXB9 gene are described for the first time. Truncating mutations (frameshifts or nonsense mutations) represent 57% of those identified, suggesting that haploinsufficiency is the basis of CS. No obvious genotype-phenotype correlation can be drawn thus far. Genetic heterogeneity is suspected, since at least 19 of the 24 patients without HLXB9 gene mutation harbor subtle phenotypic variations.

Long-term outcome, growth and digestive function in children 2 to 18 years after intestinal transplantation.

OBJECTIVE: Small bowel (SB) transplantation (Tx), long considered a rescue therapy for patients with intestinal failure, is now a well recognised alternative treatment strategy to parental nutrition (PN). In this retrospective study, we analysed graft functions in 31 children after SBTx with a follow-up of 2-18 years (median 7 years). PATIENTS: Twelve children had isolated SBTx, 19 had combined liver-SBTx and 17 received an additional colon graft. Growth, nutritional markers, stool balance studies, endoscopy and graft histology were recorded every 2-3 years post-Tx. RESULTS: All children were weaned from PN after Tx and 26 children remained PN-free. Enteral nutrition was required for 14/31 (45%) patients at 2 years post-Tx. All children had high dietary energy intakes. The degree of steatorrhoea was fairly constant, with fat and energy absorption rates of 84-89%. Growth parameters revealed at transplantation a mean height Z-score of -1.17. After Tx, two-thirds of children had normal growth, whereas in one-third, Z-scores remained lower than -2, concomitant to a delayed puberty. Adult height was normal in 5/6. Endoscopy and histology analyses were normal in asymptomatic patients. Chronic rejection occurred only in non-compliant patients. Five intestinal grafts were removed 2.5-8 years post-Tx for acute or chronic rejection. CONCLUSIONS: This series indicates that long-term intestinal autonomy for up to 18 years is possible in the majority of patients after SBTx. Subnormal energy absorption and moderate steatorrhoea were often compensated for by hyperphagia, allowing normal growth and attainment of adult height. Long-term compliance is an important pre-requisite for long-term graft function.

Long-term outcome of children receiving home parenteral nutrition: a 20-year single-center experience in 302 patients.

BACKGROUND: More information is needed regarding the prognosis of children receiving home parenteral nutrition (HPN). This article describes 20-year outcome data in children receiving HPN and provides separate profiles for the major pediatric diagnostic subgroups. PATIENTS AND METHODS: This retrospective study included children who started receiving HPN between January 1, 1980, and December 31, 1999, in a single pediatric HPN center. RESULTS: A total of 302 children were recruited, 230 (76%) with primary digestive disorders and 72 (24%) with nonprimary digestive disorders. Median age at HPN onset was 1.5 years. Median duration of HPN was 1.3 years. By January 1, 2000, 54% had weaned from HPN, 26% were still receiving HPN, 16% had died, and 4% had undergone intestinal transplantation. The survival probabilities at 2, 5, 10, and 15 years were 97%, 89%, 81%, and 72%, respectively. The likelihood and cause of death depended on the underlying diagnosis. Nine percent of children with primary digestive disorders died, 24% from their primary disease and 48% from liver disease or sepsis. Children with intractable diarrhea of infancy had the highest mortality rate (25%) and the highest incidence of liver disease (48%; P = 0.0002). Thirty-eight percent of children with primary nondigestive diseases died, 94% from their primary disease and 6% from liver disease or sepsis. CONCLUSIONS: Outcome and survival of children receiving HPN are mainly determined by their underlying diagnosis. Nearly all children with primary digestive disease survive if referred early to an expert center.

Factors influencing outcome after intestinal transplantation in children.

We evaluated 131 patients (6 months-14 years) who experienced 21 deaths before listing, 11 continuing on the waiting list, 38 well on home parenteral nutrition, 6 off parenteral nutrition and 59 transplanted (20 girls) aged 2.5 to 15 years, (18 >7 years). They received cadaveric isolated intestine (ITx, n = 31) or liver-small bowel (LITx, n = 32), including right colon (n = 43; 23 LITx) for short bowel (n = 19), enteropathy (n = 20), Hirschsprung (n = 14), or pseudo-obstruction (n = 6). Treatment included tacrolimus, steroids, azathioprine, or interleukin-2 blockers. After 6 months to 10.5 years, the patient and graft survivals were 75% and 54%. Sixteen patients (10 LITx) died within 3 months from surgery (n = 3), bacterial (n = 5) or fungal (n = 6) sepsis, or posttransplant lymphoproliferative disorder (n = 2). Rejection occurred in 27 patients, including 10 steroid-resistant episodes requiring antilymphoglobulins. The grafts were removed due to uncontrolled rejection in seven ITx recipients. Surgical complications were observed in 38 recipients (25 LSBTx) within 2 months, including bacterial (n = 22) or fungal (n = 11) sepsis, cytomegalovirus disease (n=12), adenovirus (n = 11), or posttransplant lymphoproliferative disorder (n = 12). Forty-two children (19 LSBTx) are alive. Weaning from parenteral nutrition was achieved after 42 days (median). Factors related to death or graft loss were pre-Tx surgery (P < .01), pseudo-obstruction (P < .01), age over 7 years (P < .03), fungal sepsis (P < .03), steroid resistant rejection (P < .05), hospitalized versus home patient (P < .01), and retransplantation (P < .05). Colon transplant did not affect the outcome. Interleukin-2 blockers improved isolated ITx (P < .05). Early referral and close monitoring of intestinal failure and related disorders are mandatory to achieve successful ITx.

Prenatal diagnosis of pulmonary sequestration using three-dimensional power Doppler ultrasound.

OBJECTIVE: To investigate the contribution of three-dimensional power Doppler ultrasound to the prenatal diagnosis of pulmonary sequestration. METHODS: Prenatal three-dimensional power Doppler ultrasound was used to screen for an abnormal pulmonary blood supply in eight fetuses with hyperechogenic lung lesions and to image the pulmonary blood supply in 50 normal controls. A comparison was made with postnatal findings. RESULTS: Postnatally the eight pulmonary lesions were found to be an isolated pulmonary sequestration (n = 3), a microcystic congenital adenomatoid malformation (n = 4), and a mixed (macrocystic and microcystic) congenital adenomatoid malformation (n = 1). Prenatal three-dimensional power Doppler ultrasound demonstrated an abnormal blood supply in all cases of pulmonary sequestration and in none of the other cases. Among the three cases that turned out to be pulmonary sequestrations, conventional two-dimensional ultrasound failed to identify the feeding vessel in one case and identified it at a later stage of gestation than did three-dimensional power Doppler in the other two. CONCLUSION: Prenatal three-dimensional power Doppler ultrasound may be useful in identifying the feeding vessel and thus establishing the diagnosis of pulmonary sequestration in the presence of a hyperechogenic pulmonary lesion, allowing its differentiation from congenital cystic adenomatoid malformation.