Follow-up ultrasonographic findings among children treated conservatively for uncomplicated acute appendicitis.

BACKGROUND: Ultrasound is an accurate tool for diagnosing acute appendicitis. Conservative treatment for uncomplicated acute appendicitis is feasible and safe in children. However, no sonographic follow-up results from children with nonoperatively managed acute appendicitis have been reported. OBJECTIVE: To describe the sonographic appearance of the appendix at follow-up ultrasound and to attempt to identify signs predictive of recurrent acute appendicitis. MATERIALS AND METHODS: Children diagnosed with uncomplicated acute appendicitis and treated conservatively in our hospital from 2014 to 2019, and who presented for follow-up ultrasound at 3, 6 and 9 months, were included in our study. Clinical, laboratory and ultrasound data were recorded. RESULTS: By the end of follow-up, 29 (14.2%) of 204 children in the cohort had developed recurrent acute appendicitis and 175 had recovered uneventfully. On follow-up ultrasound, appendiceal diameter measured > 6 mm in 56/204 (27.5%) cases at 3 months and in 9/26 (34.5%) at 6 months. After 3 months, 102/204 (50%) children had normal appendiceal diameter on ultrasound. Appendiceal diameter > 6 mm was associated with intraluminal fluid or sludge in the appendiceal lumen at 3- and 6-month follow-up (P < 0.001, P = 0.002, respectively). Comparing cases with and without recurrence, at 3-month follow-up, appendiceal diameter > 6 mm was found in 17/29 (58.6%) cases vs. 39/175 (22.3%), respectively (P < 0.001). Appendiceal diameter returned to normal in 12/19 (63.2%) cases in the nonrecurrent acute appendicitis group compared with 2/7 (28.6%) in the recurrent acute appendicitis group (P = 0.05) at the 6-month follow-up. Intraluminal fluid or sludge was detected more frequently in the recurrent acute appendicitis versus the nonrecurrent acute appendicitis group at 3- (P < 0.001) and 6-month (P = 0.001) follow-up. CONCLUSION: Progressive normalization of appendiceal diameter was noted on follow-up ultrasound. The prevalence of both appendiceal diameter > 6 mm and intraluminal fluid or sludge were found to be increased in children who later developed recurrent acute appendicitis. Ultrasound appears to be a useful tool for follow-up in children with conservatively treated uncomplicated acute appendicitis and possibly might help predict recurrence.

Acute appendicitis in children: Reexamining indications for conservative treatment - A large prospective analysis.

INTRODUCTION: Conservative antibiotic treatment (CAT) for uncomplicated acute appendicitis (AUA) in children has been proven safe and efficacious. However, as data accumulate, high rates of recurrent appendicitis and subsequent appendectomy have been reported. This prospective longitudinal study evaluated risk-factors for recurrent AUA after CAT in a large cohort, with long-term follow-up. MATERIALS AND METHODS: Children ages 5 to 16 years admitted to the Department of Pediatric Surgery from 2014 through 2018, diagnosed with AUA were eligible for CAT. We recorded their age, appendix outer diameter, white blood cell counts, C-reactive protein and other related signs and symptoms associated with AUA. Clinical and ultrasonographic follow-up was carried out until follow-up data collection ceased according to the study design (2014-2019). RESULTS: The cohort included 646 children who were initially treated successfully with CAT. Among them, 180 (28%) were readmitted for recurrent acute appendicitis during the follow-up period and 138 (21%) eventually had appendectomy. Overall success of 79% for CAT was recorded in this cohort. A multivariable model including; age, sex, appendiceal diameter, WBC and CRP, found the factors of older age, larger outer appendiceal diameter and high WBC counts significantly related to appendectomy during the follow-up period. We offer a decision tree model to predict appendectomy probabilities for patients based on their prognostic measurements. CONCLUSION: CAT in AUA in children should consider older age, larger outer appendiceal diameter and high WBC counts as risk-factors for recurrent AUA and subsequent appendectomy. The proposed decision tree model may help both clinicians and parents before CAT is chosen. LEVEL OF EVIDENCE: Level 2.

Blunt High-Grade Pancreatic Injury in Children: A 20-Year Experience in Two Pediatric Surgical Centers.

BACKGROUND: Pancreatic trauma is uncommon in pediatric patients and presents diagnostic and therapeutic challenges. While non-operative management (NOM) of minor pancreatic injuries is well accepted, the management of major pancreatic injuries remains controversial. OBJECTIVES: To evaluate management strategies for major blunt pancreatic injury in children. METHODS: Data were retrospectively collected for all children treated for grade III or higher pancreatic injury due to blunt abdominal trauma from 1992 to 2015 at two medical centers. Data included demographics, mechanism of injury, laboratory and imaging studies, management strategy, clinical course, operative findings, and outcome. RESULTS: The cohort included seven boys and four girls aged 4-15 years old (median 9). Six patients had associated abdominal (mainly liver, n=3) injuries. The main mechanism of injury was bicycle (handlebar) trauma (n=6). Five patients had grade III injury and six had grade IV. The highest mean amylase level was recorded at 48 hours after injury (1418 U/L). Management strategies included conservative (n=5) and operative treatment (n=6): distal (n=3) and central (n=1) pancreatectomy, drainage only (n=2) based on the computed tomography findings and patient hemodynamic stability. Pseudocyst developed in all NOM patients (n=5) and two OM cases, and one patient developed a pancreatic fistula. There were no differences in average length of hospital stay. CONCLUSIONS: NOM of high-grade blunt pancreatic injury in children may pose a higher risk of pseudocyst formation than OM, with a similar hospitalization time. However, pseudocyst is a relatively benign complication with a high rate of spontaneous resolution with no need for surgical intervention.

Does Maternal Omega 3 Supplementation Protect Against Infantile Hypertrophic Pyloric Stenosis?

OBJECTIVES: Infantile hypertrophic pyloric stenosis (IHPS) is potentially life threatening. The etiology of IHPS remains unknown and many risk factors have been reported. We aimed to assess the prevalence of known risk factors and investigate maternal nutrition and habits as possible additional risk factors for IHPS. METHODS: This case-control study includes mothers of infants diagnosed with IHPS and control mothers of infants, age 2 to 11 months, hospitalized in the pediatric department due to other conditions. Cases of IHPS were identified by review of all infants diagnosed with IHPS and operated upon in 2010 to 2016 at 2 major hospitals in central Israel. Data regarding potential risk factors were collected via questionnaires in both study groups. RESULTS: Sixty-six cases and 67 controls were included in the study. Maternal omega 3 supplement consumption during pregnancy was significantly less common among cases of IHPS as compared with controls (P = 0.031). Consumption of omega 3 supplement was defined as consumption of at least 1 to 2 per week during the pregnancy period. Following adjustment for known risk factors, including male sex and maternal smoking, maternal omega 3 supplement consumption remained associated with a significantly lower risk of developing IHPS (odds ratio = 0.303, 95% confidence interval 0.111-0.828, P = 0.02). CONCLUSIONS: Maternal omega 3 supplement consumption during pregnancy was associated with a significantly reduced risk of IHPS. Further studies are needed to support these results and investigate possible mechanisms of the effect of omega 3.

Water chemistry reveals a significant decline in coral calcification rates in the southern Red Sea.

Experimental and field evidence support the assumption that global warming and ocean acidification is decreasing rates of calcification in the oceans. Local measurements of coral growth rates in reefs from various locations have suggested a decline of ~6-10% per decade since the late 1990's. Here, by measuring open water strontium-to-alkalinity ratios along the Red Sea, we show that the net contribution of hermatypic corals to the CaCO3 budget of the southern and central Red Sea declined by ~100% between 1998 and 2015 and remained low between 2015 and 2018. Measured differences in total alkalinity of the Red Sea surface water indicate a 26 ± 16% decline in total CaCO3 deposition rates along the basin. These findings suggest that coral reefs of the southern Red Sea are under severe stress and demonstrate the strength of geochemical measurements as cost-effective indicators for calcification trends on regional scales.

Conservative antibiotic treatment for acute uncomplicated appendicitis is feasible.

PURPOSE: Appendectomy versus conservative antibiotic treatment (CAT) for children with acute uncomplicated appendicitis (AUA) remains unresolved, with concerns regarding the practicality of CAT. We analyzed our center's experience with CAT for AUA, using a protocol with strict inclusion, exclusion and treatment criteria. METHODS: Non-randomized, prospective cohort study included all children admitted betwee 2014 and 2016, with clinical and laboratory tests suspicious for AUA. Data collected included clinical signs and symptoms; laboratory, ultrasound and pathology results. Follow-up was conducted through clinic visits, telephone conversations and national registry analysis. RESULTS: Included in CAT: 362 children, 19 underwent appendectomy within 1-2 days. Overall, 75 were readmitted for recurrent acute appendicitis during 22 months (6-43) follow-up. Thirty were treated successfully with antibiotics a second time. The remaining 45 had appendectomy. Overall, 86.8% underwent CAT with no surgery. Histology of all recurrent AUA revealed no perforations. CONCLUSION: We confirm the feasibility of conservative management of AUA in children. A rigorous diagnostic plan with strict inclusion and exclusion criteria will lead to high success rate of CAT with a strong safety profile. CAT does not compete with surgery or render appendectomy unnecessary. It is a safe alternative to surgery in selected cases.

Conservative treatment in uncomplicated acute appendicitis: reassessment of practice safety.

The success rate of conservative treatment for children with uncomplicated appendicitis was prospectively evaluated among 197 children. All who received intravenous antibiotics for 3-5 days, and if symptoms resolved, were discharged home on oral antibiotics for 5 days. Failure rate, symptoms, laboratory signs, and sonographic findings were evaluated for prognostic markers of treatment failure. Children were followed for 18 months. The success rate of conservative treatment was 87%, with shorter hospital stays compared to children who eventually needed surgery (72 [60-84] vs. 84 h [72-126], P = 0.001). Vomiting and/or nausea and intraluminal fluid on sonography were the only prognostic signs of failed treatment (P = 0.028 and P = 0.0001, respectively). After multi-regression analysis, intraluminal fluid was the only prognostic sign for failed treatment (odds ratio = 10.2; 95% CI 3.3-31.8, P = 0.001). Patients who failed conservative treatment were successfully operated without significant morbidity. Pathology findings were compatible with acute or subacute inflammation in 94% of operated AA, with no perforated appendices. CONCLUSION: When applying rigorous criteria for children with uncomplicated appendicitis, a high success rate can be achieved with conservative treatment. Those who fail conservative treatment have a benign medical course without serious complications. Intraluminal fluid may increase risk for conservative treatment failure. What is Known: • Conservative treatment in uncomplicated acute appendicitis is a reasonable alternative to appendectomy. What is New: • Using rigorous criteria for conservative treatment in uncomplicated acute appendicitis is safe and feasible. • Intraluminal fluid should be considered a contraindication to conservative treatment.

Iron homeostasis after blood transfusion in stable preterm infants - an observational study.

AIM: To evaluate the short-term effects of blood transfusion on iron status [hemoglobin, ferritin, soluble transferrin receptor (sTfR), and reticulocyte count], hepcidin, and erythropoietin in stable preterm infants. METHOD: Sixty-three preterm infants treated with red blood cell transfusions (RBCTs) were included. Venous blood samples were collected before and within 24 h after each transfusion. RESULTS: Hemoglobin concentration increased after RBCT (7.2±1.2 g/dL vs. 13.7±2.3 g/dL, P=0.02), as well as ferritin [131 (63-110.4) ng/mL vs. 211 (125.7-299.2) ng/mL, P=0.05); reticulocyte count decreased. sTfR did not change. Hepcidin serum levels increased from 37.5 (21.3-84.7) ng/mL to 72.6 (31.3-126.2) ng/mL, (P=0.04) and erythropoietin decreased (48±19 pg/mL vs. 29±17 pg/mL, P=0.06) after RBCT. A positive linear correlation was found (R2=0.76, P=0.0001) between hepcidin and ferritin levels of post-minus-pre RBCT. Hepcidin levels increased significantly in preterm infants who received RBCT after 1 month of age compared to those who received RBCT at <1 month (P=0.03). No correlation was found between gestational age, weight appropriate for age, or length of blood storage and hepcidin levels. CONCLUSION: Preterm infants can control iron levels by regulating hepcidin and decreasing erythropoietin. This ability varies with postnatal age.

A role for conservative antibiotic treatment in early appendicitis in children.

PURPOSE: To evaluate whether antibiotics without surgery is sufficient treatment for children with clinically and ultrasonographically suspected acute appendicitis (AA). METHOD: Children with clinical, laboratory and radiological findings suspicious for AA were evaluated prospectively. Patients with mild clinical signs, without peritonitis were considered for IV followed by oral antibiotics without surgery. RESULTS: From 1 November 2013 through 30 June 2014, 45 children were diagnosed with early, acute appendicitis. Ages ranged from 4 to 15 years (mean 9.3) and 32 (75%) were boys. All had routine, clinical laboratory and ultrasound workup. Forty-two improved with antibiotic treatment and were discharged home within 3-5 days, without surgery. Three of them were operated on within 24 hours, another two underwent appendectomy for recurrent appendicitis: one at 2 weeks and the other 2 months after discharge. There was no more recurrent appendicitis in 6-14-month follow-up. CONCLUSION: Our series of patients with AA treated with antibiotics only are a product of the observation that some children improve with antibiotics alone at a stage in which surgery is still debatable. These results (89% success rate) support the conservative approach in cases of early appendicitis, without increased morbidity in failed cases.

Anorectal injuries in children: a 20-year experience in two centers.

INTRODUCTION: Anorectal injuries in children are not frequently reported and their management is challenging. This report reviews the experience in managing this type of injuries in two medical centers over 20 years. METHODS: An institutional database search for patients who were treated for anorectal injuries between 1994 and 2015 was undertaken. Twenty cases were located and medical records reviewed. This study was conducted with institutional review board approval (#572-14). RESULTS: There were 6 girls and 14 boys with ages ranging between 1 and 15 years (mean 7 years). Eleven patients sustained penetrating trauma, while nine sustained blunt trauma. The mechanism of injury was variable and associated injuries were more common in blunt trauma. Most common presenting symptoms were rectal bleeding (n = 12) and anal pain (n = 11), followed by abdominal pain in six patients. Eighteen anorectal injuries were extraperitoneal and two intraperitoneal. Among patients with extraperitoneal injuries, 12/18 were managed by primary repair with (6) or without (6) fecal diversion and 2/18 by wound irrigation and drainage with fecal diversion and delayed repair. Four patients had superficial anal and perineal injuries that were irrigated and left to heal by secondary intention. Two patients with intraperitoneal rectal injuries underwent primary repair with fecal diversion. Follow-up period ranged from 2 weeks to 8 years (mean 2 years). There were three cases of wound infection, one case of suture line leak requiring reoperation and one case of vesicorectal fistula in a patient with combined trauma of the rectum and urinary bladder. There was no mortality. Fecal continence was preserved in all patients available for follow-up evaluation. CONCLUSIONS: Primary repair of the perineal wound and anal sphincters can be performed safely in most cases given hemodynamic stability. Fecal diversion should be saved for cases with severe perineal involvement or cases with substantial associated injuries and concern of gross contamination.

Neonatal Chest Wall Rhabdomyosarcoma.

An infant was born at term with a huge chest mass diagnosed as rhabdomyosarcoma. Treatment consisted of surgical resection and chemotherapy. We describe this very rare congenital mass and the problematic therapeutic management of such a tumor in a newborn.

Basin-scale estimates of pelagic and coral reef calcification in the Red Sea and Western Indian Ocean.

Basin-scale calcification rates are highly important in assessments of the global oceanic carbon cycle. Traditionally, such estimates were based on rates of sedimentation measured with sediment traps or in deep sea cores. Here we estimated CaCO3 precipitation rates in the surface water of the Red Sea from total alkalinity depletion along their axial flow using the water flux in the straits of Bab el Mandeb. The relative contribution of coral reefs and open sea plankton were calculated by fitting a Rayleigh distillation model to the increase in the strontium to calcium ratio. We estimate the net amount of CaCO3 precipitated in the Red Sea to be 7.3 ± 0.4·10(10) kg·y(-1) of which 80 ± 5% is by pelagic calcareous plankton and 20 ± 5% is by the flourishing coastal coral reefs. This estimate for pelagic calcification rate is up to 40% higher than published sedimentary CaCO3 accumulation rates for the region. The calcification rate of the Gulf of Aden was estimated by the Rayleigh model to be ∼1/2 of the Red Sea, and in the northwestern Indian Ocean, it was smaller than our detection limit. The results of this study suggest that variations of major ions on a basin scale may potentially help in assessing long-term effects of ocean acidification on carbonate deposition by marine organisms.

Does Staphylococcus aureus nasal carriage require eradication prior to elective ambulatory surgery in children?

PURPOSE: Rates of community-associated Staphylococcus aureus, and particularly of methicillin-resistant Staphylococcus aureus (MRSA) in children, have increased in recent years. We investigated rates of nasal colonization of S. aureus, and a possible correlation between nasal carriage and wound infection. METHODS: A prospective study of children scheduled for elective day-care surgical procedures between January 2008 and December 2012 at one medical center. Nasal swabs were taken before surgery, and follow-up was performed 1-2 weeks following surgery. RESULTS: Of 1,127 children (median age 2 years, 70.6% males), positive nasal swabs were detected in 228 (20.2%). Rates of S. aureus nasal carriage were lowest for ages 6 months to 2 years and highest for ages 4-11 years. Child's sex did not associate with the risk for positive nasal swabs. Positive nasal swabs for MRSA were detected in five boys (0.62% of the population). Five children (0.44%) had wound infection. None of them was a nasal carrier. CONCLUSIONS: No correlation was observed between positive nasal swabs and wound infection in children who were candidates for elective ambulatory operations. This suggests that evaluation of S. aureus nasal carriage and eradication may not be necessary in this population.

Studying the role of common membrane surface functionalities on adsorption and cleaning of organic foulants using QCM-D.

Adsorption of organic foulants on nanofiltration (NF) and reverse osmosis (RO) membrane surfaces strongly affects subsequent fouling behavior by modifying the membrane surface. In this study, impact on organic foulant adsorption of specific chemistries including those in commercial thin-film composite membranes was investigated using self-assembled monolayers with seven different ending chemical functionalities (-CH(3), -O-phenyl, -NH(2), ethylene-glycol, -COOH, -CONH(2), and -OH). Adsorption and cleaning of protein (bovine serum albumin) and polysaccharide (sodium alginate) model foulants in two solution conditions were measured using quartz crystal microbalance with dissipation monitoring, and were found to strongly depend on surface functionality. Alginate adsorption correlated with surface hydrophobicity as measured by water contact angle in air; however, adsorption of BSA on hydrophilic -COOH, -NH(2), and -CONH(2) surfaces was high and dominated by hydrogen bond formation and electrostatic attraction. Adsorption of both BSA and alginate was the fastest on -COOH, and adsorption on -NH(2) and -CONH(2) was difficult to remove by surfactant cleaning. BSA adsorption kinetics was shown to be markedly faster than that of alginate, suggesting its importance in the formation of the conditioning layer. Surface modification to render -OH or ethylene-glycol functionalities are expected to reduce membrane fouling.

Development of an oligoamide coating as a surface mimetic for aromatic polyamide films used in reverse osmosis membranes.

We developed a method for the in situ synthesis of an oligoamide coating on gold. The resultant surface chemical composition, wettability, and chemical nature were comparable to aromatic polyamide films used as reverse osmosis membranes. Hence, the oligoamide wafer may be used in adsorption/fouling studies as a surface mimetic of reverse osmosis membranes.

Effect of surface-exposed chemical groups on calcium-phosphate mineralization in water-treatment systems.

Calcium-phosphate-scale formation on reverse osmosis (RO) membranes is a major limiting factor for cost-effective desalination of wastewater. We determined the effects of various organic chemical groups found on membrane surfaces on calcium-phosphate scaling. Langmuir films exposing different functional groups were equilibrated with a solution simulating the ionic profile of secondary effluent (SSE). Surface pressure-area (Langmuir) isotherms combined with ICP elemental analyses of the interfacial precipitate suggested acceleration of calcium-phosphate mineralization by the surface functional groups in the order: PO(4) > COOH ∼ NH(2) > COOH:NH(2) (1:1) > OH > ethylene glycol. Immersion of gold-coated silicon wafers self-assembled with different alkanethiols in SSE solution showed formation of a hydroxyapatite precipitate by X-ray diffraction and ATR-IR analysis. Data showed diverse influences of functional groups on mineralization, implying low calcium-phosphate scaling for uncharged surfaces or surfaces coated with both positively and negatively charged groups. This information is valuable for understanding scaling processes, and for designing of novel low-scaling membranes for water desalination.

Do children tolerate thoracoscopic sympathectomy better than adults?

Palmar hyperhidrosis (PHH) is fairly a common condition, which is treatable by thoracoscopic sympathectomy (TS). Compensatory sweating (CS) is a major side effect of TS. We compared the TS procedure's long-term success, patient's satisfaction and complications between children (< or =14 years of age) and adolescents and adults (> or =15 years of age). A chart review of the patients who had undergone TS at three medical centers (Hillel Yaffe, Soroka and Bnai-Zion) who could be contacted and agreed to reply to a detailed telephone questionnaire yielded 325 patients with a >24-month follow-up. There were 116 children and 209 adolescents and adults with a follow-up of 2-8 years. Most participants (96.3%) reported complete or reasonable symptomatic relief. The long-term postoperative satisfaction was high (84.5%), and significantly higher among children (92.2%) compared to adolescents and adults (80.7%) (P = 0.005). CS appeared within 6 months postoperatively in 81.8% of all the patients but significantly less in children (69.8%) compared to the others (88.5%; P < 0.001). CS increased with time in 12% of the participants, but decreased in 20.8% of the children versus 10.5% of the others (P = 0.034), usually within the first two postoperative years. The severity of the CS was also lower in children: it was absent or mild in 54.3% of the children versus 38.0% of the others, and moderate or severe in 45.7 versus 62%, respectively (P = 0.004). Fifty-one percent of the participants claimed that their quality of life decreased moderately or severely as a result of CS, but only one-third of them (7.9% children vs. 22.4% others, P = 0.001) would not have undergone the operation in retrospect. Thoracoscopic sympathectomy relieves PHH in most cases. Most patients prefer relief from PHH even at the cost of moderate or severe CS. The rate of CS and its severity is tolerated better by children, and their postoperative satisfaction is higher than that of adolescents and adults. Therefore, unless otherwise contraindicated, we recommend doing TS as early as possibly.

Compensatory sweating after thoracoscopic sympathectomy: an acceptable trade-off.

BACKGROUND/PURPOSE: Palmar hyperhidrosis is a fairly common condition that is treatable by thoracoscopic sympathectomy (TS). Compensatory sweating (CS) is a major side effect of TS. We surveyed post-TS patients to determine the procedure's long-term success, satisfaction, complications, the natural history of CS, and whether those with CS would still have undergone the procedure. METHODS: A chart review of all patients who had undergone TS at 2 medical centers yielded 621 patients (mean age, 16.1 years) with a follow-up of more than 24 months: 265 (43%) could be contacted and agreed to reply to a detailed telephone questionnaire. RESULTS: Most participants (97%) reported complete (89.4%) or reasonable (7.6%) symptomatic relief. The long-term postoperative satisfaction was high (84.5%). Forty-one percent of the participants claimed that their quality of life decreased moderately or severely as a result of CS. Only 19.6% would not have undergone the operation in retrospect; there was a significant interesting difference regarding this issue between adults (31.4%) and children (8.8%). The extent of the CS did not change with time in 70% of the patients. It exacerbated in 10% and it diminished in 20%, usually within the first 2 postoperative years. CONCLUSIONS: Thoracoscopic sympathectomy relieves hyperhidrosis in most cases. Patients prefer relief from palmar hyperhidrosis even at the cost of a high rate of CS. Hyperhidrosis is not a self-limiting condition, and we recommend not postponing TS until adulthood.

Allele dosage-dependent penetrance of RET proto-oncogene in an Israeli-Arab inbred family segregating Hirschsprung disease.

Hirschsprung disease (HSCR) is characterised by intestinal obstruction resulting from an absence of ganglion cells in the intestinal tract. The mutations in the major gene, RET, associated with isolated HSCR, are dominant loss-of-function mutations with incomplete penetrance and variable expressivity. We have ascertained a large inbred Israeli-Arab family segregating HSCR. Sequencing of the RET gene showed a splicing mutation, IVS6+5G- >A, in the homozygous state in all the females with severe forms of HSCR and in the heterozygous state in the male patient with short-segment HSCR. The recently described hypomorphic-RET predisposing allele, rs2435357, was transmitted in the heterozygous state to the male patient, but was not transmitted to the three affected females. Although the heterozygous IVS6+5G- >A is of low-penetrance for short-segment HSCR disease, the homozygous state is fully penetrant for total aganglionosis or long-segment HSCR. As in other inbred populations segregating a weakly penetrant RET allele (Mennonite), our findings support the hypothesis that the penetrance of RET gene mutations for the HSCR phenotype depends on: (i) the nature of the mutation, (ii) the allele dosage and (iii) modifier-loci.