PSU Volume 60 NO 01 JANUARY 2023

Canal of Nuck Hydrocele

There is a difference in the content of the inguinal canal between males and females. During development of the female fetus the round ligament of the uterus descends into the inguinal canal to the labium major. The peritoneal fold that descends with the round ligament accompanying the gubernaculum during descend is named the canal of Nuck. This structure is homologous to the processus vaginalis of the male anatomy. In normal female development, the canal of Nuck obliterates in a superior to inferior direction, a process that begins at about the 7th month of gestation and is completed by about one year of age. If the canal begins normal closure at the superior portion but remains patent in the inferior portion fluid can accumulate and develop into an encysted hydrocele of the canal of Nuck. Should this communication fail to close completely it results in a patent canal of Nuck and the development of an indirect hernia or communicating hydrocele. Hydroceles of the canal of Nuck are very rare. Herniation of the ovary is most common, occurring in up to 20% of cases possibly due to tension from the round and ovarian ligaments. Herniation of an ovary carries a risk of torsion on the axis of the vascular pedicle, a complication that occurs in up to a third of patients with a herniated ovary. In females a hydrocele of the canal of Nuck presents as a painless, translucent, fluctuating, and non-reducible swelling in the inguinal area and labium majora most often in a girl younger than 5 years of age. The prevalence is even higher in premature infants. The condition more commonly occurs on the right side, but up to 10% of cases are bilateral. Hydrocele of the canal of Nuck is classified into three types. The most common type corresponds to an encysted hydrocele of the cord in which no communication with the peritoneal cavity occurs, forming an encysted fluid collection along the tract of descend from the inguinal ring to the testis or labia majora. The second type corresponds to communicating hydrocele when there is a persistent reducible communication with the peritoneal cavity. The third type is a combination of the previous two as a result of the inguinal ring constricting the hydrocele like a belt so that part is communicating and part is enclosed, giving this type the name of hourglass type. This type of hydrocele is bound to trauma and infection of the residual hematoma created causing symptoms of pain and tenderness on the affected inguinolabial side. If the canal of Nuck as normal evagination of the parietal abdominal wall does not disappear, it causes an indirect inguinal hernia or hydrocele of the canal of Nuck. The canal of Nuck is derived from the abdominal wall and divided into two layers. The outer wall histologically consists of a fibrous form of various thickness, including smooth muscle fibers, and the inner wall consists of single-layered mesothelial cells. When the secretion and absorption of fluid become unbalanced in the secretory membrane on the inner wall, a hydrocele forms due to swelling of the pouch. This hypersecretion can be caused by infection, injury, inappropriate lymphatic drainage or a combination of these factors. Hydrocele of the canal of Nuck should be considered in differential diagnosis for inguinal swelling in a girl. The differential diagnosis also includes indirect inguinal hernia, femoral hernia, abscess, tender adenopathy, Bartholin's cyst, posttraumatic hematoma and even a cystic lymphangioma. Evaluation using US or MRI is utilized to reach a correct diagnosis. US is the preferred modality of diagnosis. An encysted hydrocele most often contains anechoic fluid usually with an elongated morphology. A hernia of the canal of Nuck may contain peritoneal fluid, omental fat, ovary, fallopian tube, uterus, bowel, or urinary bladder. Management of asymptomatic hydrocele or a canal of Nuck hernia requires surgery consisting of dissection of the hydrocele and high ligation of the hernia or hydrocele sac including closure of the deep inguinal ring. The presence of an ovary within the canal of Nuck warrants early surgical intervention to avoid risk of torsion and ovarian loss. The closure of the hydrocele or hernia can be performed laparoscopically.  

References:
1- Mandhan P, Raouf Z, Bhatti K: Infected hydrocele of the canal of nuck. Case Rep Urol. 2013;2013:275257. doi: 10.1155/2013/275257. Epub 2013 Dec 4.
2- Rees MA, Squires JE, Tadros S, Squires JH: Canal of Nuck hernia: a multimodality imaging review. Pediatr Radiol. 47(8):893-898, 2017
3- AlSaleh N, ALMaghrabi A, Banaja A: Hydrocele of the canal of Nuck. J Ped Surg Case Reports. 29: 36-38, 2018
4- Chan D, Kwon JK, Lagomarsino EM, Veltkamp JG, Yang MS, Pfeifer CM: Canal of Nuck hernias. Acta Radiol Open. 8(12): 1-5, 2019
5- Wang L, Maejima T, Fukahori S, Shun K, Yoshikawa D, Kono T: Laparoscopic surgical treatment for hydrocele of canal of Nuck: A case report and literature review. Surg Case Rep. 13;7(1):121, 2021
6- Keeratibharat N, Chansangrat J: Hydrocele of the Canal of Nuck: A Review. Cureus. 2022 Apr 2;14(4):e23757. doi: 10.7759/cureus.23757. eCollection 2022

Febrile Neutropenia

Febrile neutropenia (FN) is a common life-threatening complication of management of children with malignancy occurring in approximately one third of episodes of neutropenia. Febrile neutropenia is the occurrence of fever during a neutropenic episode. Neutropenia is defined as an absolute neutrophil count of < 500 cells/mm3 or expected to decrease to < 500 cells/mm3 during the next 48 hours. Fever is defined as a single oral temperature measurement greater than 38.5 degree centigrade sustained over a one-hour period. FN remains as one of the most concerning complication of cancer chemotherapy, being a major cause of morbidity and mortality if not managed promptly. The primary anatomic sites of infection include the gastrointestinal tract since chemotherapy induces mucosal damage allowing invasion of opportunistic organisms. Vascular access also provides a portal of entrance. In children upper respiratory tract infections are the most frequent clinically documented infections. Fever is often the sole sign of occult infection in the neutropenic host. Over time a shift has occurred from FN associated mainly with gram-negative bacteria to FN associated with gram-positive organisms. Also, an increase in antibiotic resistance strains such as beta-lactamase producing gram negative bacteria, vancomycin resistant enterococci and methicillin resistant staph aureus. Fungal infections are rarely detected at the beginning of a febrile neutropenic episode. Risk is stratified in FN into low and high risk. Factors used for risk stratification include durations of neutropenia (> 10 days), depth of neutropenia (< 100/mm3), type of malignancy, state of disease (remission, progressive disease, recurrence), bone marrow involvement, type of management, and additional associated conditions. Relative risk of infection is related to both the degree and duration of neutropenia, with risk of infection greater in neutrophil counts < 500 cells/mm3 and greatest with < 100 cells/mm3, and children with longer duration of neutropenia (> 7-10 days). Low risk patients have good performance status, few comorbid conditions, adequate hepatic, and renal function, with an expected neutropenic duration of less than seven days. High risk patients have clinical signs of hypotension, pneumonia, new onset abdominal pain, renal or hepatic changes, and neurological changes with an expected duration of neutropenia beyond seven days. Initial evaluation includes history, physical exam, blood cultures, urinalysis, urine culture, stool culture, ESR, CRP, CBC, and biochemistry (CMP). Interleukins (IL)-6, IL-8, IL-10, CRP and procalcitonin (PCT) are predictive markers of bacteremia and severe sepsis. The combination of an elevated PCT and IL-10 has a sensitivity of 100% and specificity of 89% for the prediction of initial bacteremia. Procalcitonin is a useful marker for early diagnosis of sepsis and during treatment response. With respiratory symptoms a chest film is in order. Patients with prolonged FN and high risk are recommended to under thoracic high-resolution CT to reveal evidence of fungal infection. US might be helpful for diagnosis of hepatosplenic fungal infection. Standard of care in FN high risk children include hospitalization and treatment with intravenous wide spectrum empiric antibiotics until fever subsides and neutrophil count > 500 cells/mm3. Empiric monotherapy could include antipseudomonal penicillin (piperacillin-tazobactam and ticarcillin-clavunate acid), antipseudomonal cephalosporins (cefepime, ceftazidime) and carbapenems (meropenem or imipenem). No difference in treatment failure, mortality or adverse reaction is seen when penicillinÕs are compared to cephalosporin or carbapenems. Carbapenems are associated with more episodes of pseudomembranous colitis. Double therapy should be used depending on culture results or clinical signs. In patients with persistent fevers who become clinically unstable, the initial antibacterial therapy should be escalated to include coverage for resistant gram negative, gram positive and anaerobic bacteria. In low-risk patients intravenous antibiotics may be initiated and continued in the hospital or as outpatient if there can be adequate follow-up. Patients recovering phagocyte counts are good candidate for outpatient management. Oral antibiotics used in pediatrics studies are fluoroquinolone monotherapy, fluoroquinolone and amoxicillin-clavunate, and cefixime. Colony stimulating factors (G-CSF) may be used as primary or secondary prophylaxis in children with cancer and continued during FN. In neutropenic high-risk children, empiric antifungal treatment should be given for persistent or recurrent fever of unclear etiology that is unresponsive to prolonged antibiotic therapy. Amphotericin-B or caspofungin is efficient in children for empiric antifungal therapy. These patients include those with acute myeloid leukemia, high risk acute lymphoblastic leukemia, relapsed acute leukemia, or children undergoing allogeneic hematopoietic stem cell transplantation.     

References:
1- Lehrnbecher T, Robinson P, Fisher B, et al: Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update. J Clin Oncol. 35(18):2082-2094, 2017
2- Kebudi R, Kizilocak H. Febrile Neutropenia in Children with Cancer: Approach to Diagnosis and Treatment. Curr Pediatr Rev. 14(3):204-209, 2018
3- Alali M, David MZ, Danziger-Isakov LA, Elmuti L, Bhagat PH, Bartlett AH: Pediatric Febrile Neutropenia: Change in Etiology of Bacteremia, Empiric Choice of Therapy and Clinical Outcomes. J Pediatr Hematol Oncol. 42(6):e445-e451, 2020
4- Alali M, David MZ, Ham SA, Danziger-Isakov L, Pisano J. Febrile Neutropenia Syndromes in Children: Risk Factors and Outcomes of Primary, Prolonged, and Recurrent Fever. J Pediatr Hematol Oncol. 2021 Oct 1;43(7):e962-e971
5- Haeusler GM, De Abreu Lourenco R, et al: Managing low-risk febrile neutropenia in children in the time of COVID-19: What matters to parents and clinicians. J Paediatr Child Health. 57(6):826-834, 2021
6- Doerflinger M, Haeusler GM, Li-Wai-Suen CSN, et al: Procalcitonin and Interleukin-10 May Assist in Early Prediction of Bacteraemia in Children With Cancer and Febrile Neutropenia. Front Immunol. 2021 May 20;12:641879. doi: 10.3389

Umbilical Hernias

Umbilical hernias in children are very common surgical condition affecting approximately 800,000 children in the Unites States each year. They result from the incomplete closure of the umbilical ring and are found in up to 10-30% of newborns. The incidence of umbilical hernia is associated with race, birth weight and certain syndromes. African American infants are 6-10 times more likely than Caucasian infant to have an umbilical hernia. Infants weighting less than 1200 gm. are nearly four times more likely to have an umbilical defect. Children with Beckwith-Wiedemann and Down syndrome also have an increased risk of umbilical defects. Umbilical hernia repair is the most common elective general surgery procedure performed in children between one and 17 years old. Most of these hernias close spontaneously within the first few two years of life. The likehood of a defect closing depends on the size of the defect and the age of the child. Due to the high rate of spontaneous closure associated with a low rate of incarceration and other complications is the main reason why expectant management is recommended in infants and young children. Management of incarcerated or strangulated hernias includes surgical repair at the time of presentation or within one to 2 weeks if the incarcerated umbilical hernia can be manually reduced. Age of two years is the earliest age when surgical repair of asymptomatic umbilical hernia should be considered should the defect cause symptoms of pain, bowel obstruction, or incarceration. Though it is widely accepted that most asymptomatic umbilical hernia should be repaired after age of four, the reality is that greater than 50% of children are three years of age or younger at the time of repair. The main relative indications for early repair of umbilical hernia include a fascial defect greater than 2 cm, enlargement of the defect over time, or the presence of a proboscoid hernia. A proboscoid umbilical hernia have a small defect with a large amount of redundant overlying skin which many times cause significant stress to parents. Parental anxiety over a complication of the cosmetic appearance of the hernia are other reason surgeons repair them early in life. Public insurance, lower income, and female sex are independently associated with repair of asymptomatic umbilical hernias in children earlier than recommended by current guidelines. A fact probably associated with more visits to the ER by these group of patients. Acute or chronic intermittent incarceration episodes and evident strangulation which per se are extremely rare events are absolute indications for umbilical hernia repair as soon as possible. Surgeons may be incentivized to optimize clinical revenue, or motivated or comply with expectations set by referring providers that early repair should be performed. The diagnosis of an umbilical hernia is with the physical exam. The diameter of the defect and the length of the hernia should be measured and recorded to compare findings with the next follow-up visit. The rate of recurrence and unplanned related hospital revisits after pediatric umbilical hernia repair are low, though patients less than 4 years of age are at a higher risk of both recurrence and unplanned hospital cost when compared with children repaired between 4 and 10 years of age The main reason for these findings is due to children having larger fascial defect and less developed fascia, with lower tensile strength than older children. Repair of an umbilical hernia is typically done through a curved infraumbilical incision as an outpatient procedure. The umbilical stalk is dissected from the skin and inverted toward the abdominal cavity. The fascial defect is closed with interrupted transverse absorbable sutures. The umbilicus is tackled to the fascia and the skin closed. Proboscoid umbilical hernia with excess of skin should undergo umbilicoplasty techniques of which there are several. Repair should be performed before school age to avoid psychological disturbances for the child. Laparoscopic umbilical hernia repair has been described and it entails making two lateral port incisions. Other surgeons use a transumbilical technique repair of the defect.

References:
1- Halleran DR, Minneci PC, Cooper JN: Association between Age and Umbilical Hernia Repair Outcomes in Children: A Multistate Population-Based Cohort Study. J Pediatr. 217:125-130, 2020
2- Hills-Dunlap JL, Melvin P, Graham DA, Anandalwar SP, Kashtan MA, Rangel SJ: Variation in surgical management of asymptomatic umbilical hernia at freestanding children's hospitals. J Pediatr Surg. 55(7):1324-1329, 2020
3- Bawazir OA: A new umbilicoplasty technique for the management of large umbilical hernia in
children. Hernia. 23(6):1261-1266, 2019
4- Pallister ZS, Angotti LM, Patel VK, Pimpalwar AP: Transumbilical repair of umbilical hernia in children: The covert scar approach.  J Pediatr Surg. 54(8):1664-1667, 2019
5- Hills-Dunlap JL, Melvin P, Graham DA, Kashtan MA, Anandalwar SP, Rangel SJ: Association of Sociodemographic Factors With Adherence to Age-Specific Guidelines for Asymptomatic Umbilical Hernia Repair in Children. JAMA Pediatr. 173(7):640-647, 2019
6- Zens TJ, Rogers A, Cartmill R, et al: Age-dependent outcomes in asymptomatic umbilical hernia repair. Pediatr Surg Int. 35(4):463-468, 2019

PSU Volume 60 No 02 FEBRUARY 2023

Rectal Atresia

Colon and rectal atresia are very rare forms of bowel atresia, a congenital anomaly that results in complete blockade of the intestinal lumen. Rectal atresia (RA) is a congenital anomaly characterized by a blind-ending rectum. It is believed to arise because of an intrauterine vascular accident during fetal development. Prenatal environmental risk factors suggested to cause increased risk for developing rectal atresia include paternal smoking, maternal overweight obesity, and diabetes. The anal opening is anatomically normally positioned, reason why RA is considered separate from an anorectal malformation. Rectal stenosis refers to an anomaly where the rectum is narrowed but maintains a lumen that connects the anus and the more proximal colon. Rectal atresia occurs in 0.3-1.2% of all anorectal malformations with a male to female predominance of 7:3. RA is divided into five types. Type I consist of rectal stenosis, with type I-A being a stenotic segment, and I-B being a web with a hole. Type II there is rectal atresia with a septal defect. Type III, being the most common type, involves rectal atresia with a fibrous cord between the two ends. In Type IV rectal atresia there is a gap between the two segments. Type V is subdivided into three, with V-A being rectal atresia with stenosis, type V-B multiple rectal atresia, and type V-C has thickened Houston's valve and multiple rectal stenosis. In rectal atresia the pelvic structures are well developed. The anal canal, external sphincter, internal sphincter, and genitals are normal and well-developed. The proximal rectal pouch usually does not have fistulous connection with the urinary or genital tract. The diagnosis of rectal atresia is suspected when a temperature probe is unable to be inserted through the rectum. A rectal exam confirms the diagnosis of a blind ending rectum. Inability to insert a firm rectal tube, thermometer, or blunt Hegar dilator for more than 1 to 3 cm (mean 2 cm) from the anal skin is a clear indication of this malformation. The baby develops progressive abdominal distension, bilious vomiting, and failure to pass meconium. The diagnosis of a rectal stenosis is delayed since bowel movement are present. A contrast study is needed to diagnose a rectal stenosis showing a string of contrast passing into a larger proximal dilated rectum. It is recommended to perform an echocardiogram, spinal and renal ultrasound, along with MRI of the spine to check for associated malformations. Differential diagnosis of RA includes Hirschsprung disease, small bowel atresia, colonic atresia, small left colon syndrome, neuronal intestinal dysplasia, meconium plug and meconium ileus. A presacral mass is the most common associated condition with rectal atresia (30%). They could represent a presacral teratoma or anterior sacral meningocele. The mass should be resected during the operative procedure to repair the rectal atresia. Tethered cord syndrome can also be associated with RA. Management include diversion colostomy followed by planned repair. A distal colostogram before reconstruction is critical to confirm both the distance between the distal rectal pouch and the anal canal, as well as to verify the absence of a fistula with the urinary or genital tract. The goal of reconstruction is to achieve continence and normal bowel functionality by preserving the anal canal and sphincter mechanism. Two of the most common utilized approaches include posterior sagittal anorectoplasty (PSARP), or an endorectal-transanal pull through approach. With an PSARP a posterior sagittal incision is performed from coccyx to the posterior edge of the anus. The proximal bowel is dissected, mobilized and an anastomosis is performed with the distal rectum. Preserving the anterior anal canal avoids damage to the anterior rectal wall, dentate line, and sphincters. Regular dilatations will be needed before colostomy closure. In the transanal approach a submucosal dissection is done proximally in the atretic distal rectum, the proximal rectum mobilized and pull-through creating a new anastomosis. Alternatively, an endoscope can be utilized proximally into the rectum through the colostomy and the light utilized to guide the resection and dissection of the proximal rectum. The prognosis of repair of rectal atresia is good with adequate continence and good bowel control in most cases.       

References:
1- Stenstrom P, Clementson Kockum C, Arnbjornsson E: Rectal atresia-operative management with endoscopy and transanal approach: a case report. Minim Invasive Surg. 2011;2011:792402. doi: 10.1155/2011/792402. Epub 2011 Apr 21.
2- Hamrick M, Eradi B, Bischoff A, Louden E, Pena A, Levitt M: Rectal atresia and stenosis: unique anorectal malformations. J Pediatr Surg. 47(6):1280-4, 2012
3- Hamzaoui M, Ghribi A, Makni W, Sghairoun N, Gasmi M: Rectal and sigmoid atresia: transanal approach. J Pediatr Surg. 47(6):e41-4, 2012
4- M B, A K, I K, et al: Primary Transanal Management of Rectal Atresia in a Neonate. J Neonatal Surg. 10;5(2):20, 2016
5- Sharma S, Gupta DK: Varied facets of rectal atresia and rectal stenosis. Pediatr Surg Int. 33(8):829-836, 2-17
6- Tanaka A, Miyasaka EA: Colonic and rectal atresia.Semin Pediatr Surg. 31(1):151143., 2022

Santulli Enterostomy

In 1961, Santulli and Blanc introduced a side to end anastomosis with a proximal end enterostomy to effectively decompress the proximal bowel and permit early instillation of nutrients into the distal bowel in babies born with intestinal atresia. In the Santulli enterostomy, the proximal afferent bowel is fashioned into a stoma and anastomosed side-to-end into the distal efferent bowel. As a critical fact, the intestinal segment from the anastomosis to the skin (distal end of the afferent bowel) is constructed no more than six cm to avoid a blind loop after closure. The distal bowel is checked for patency with a water-soluble contrast enema prior to closure of the ileostomy. Bowel continuity occurs relatively rapid, can be monitored while the enterostomy acts as a safety valve in the case of distal or anastomotic obstruction. The Santulli procedure was initially described for management of intestinal atresia as a promising alternative given the high rate of complications, such s malfunction or leakage, seen in primary anastomotic attempts. Avoiding complete diversion of the distal bowel (small intestine and colon) is highlighted to further enhance intestinal motility and colonic function. The choice of using the Santulli enterostomy is made by the surgeon either because of a lasting discrepancy (greater than four to one) between bowel segments, or when the aspect of the distal bowel part of the bowel is not deemed satisfactory enough to perform an anastomosis. The Santulli enterostomy can be used for intestinal atresia, meconium ileus, midgut volvulus, necrotizing enterocolitis, multiple intestinal atresia, and colonic atresia. The Santulli enterostomy can be used to managed NEC even in very small premature infants with good overall results. It enables rapid access of the intestinal contents into the distal bowel and may promote enteral feeding and early stomal closure enabling preservation of sufficient intestinal length to avoid short bowel syndrome. The onset of stools passing through the anus after the Santulli procedure is noted approximately ten days after construction. Once anal stooling is passing, and the proximal effluent of the stoma decreases the Santulli enterostomy can be closed. Closure of the Santulli enterostomy is simple and requires very little additional resection of bowel. Though Santulli originally suggested extraperitoneal closure under local anesthesia, most of these closures are performed under general anesthesia. In meconium ileus the Santulli enterostomy has a better effect on ileostomy output as compared to loop ileostomy method. The rate of surgical complications and hospitalizations are significant lower in Santulli ileostomy as compared to loop ileostomy. The Santulli ileostomy also gives best cosmetic results with minimal complications and better that loop ileostomy method for management of uncomplicated meconium ileus. The Santulli enterostomy avoids the non-use of the distal bowel, especially the colon, restoring the enterohepatic circulation, preserving intestinal microbiota, avoiding diversion colitis, and reducing the risk of cholestasis, sodium depletion and metabolic acidosis seen in short bowel syndrome. The Santulli enterostomy can be used as a first-choice surgery any time there is risk of primary anastomotic disruption, or to manage a complicated former double enterostomy. The Santulli enterostomy has also been utilized in adultÕs patients for complicated hernias with intestinal necrosis and resection, complicated colorectal surgery that needs diverting enterostomy, mesenteric ischemic disorders which cannot be managed by primary anastomosis, trauma patients with intestinal discontinuity that needs a diverting enterostomy and even patients with gynecologic malignancies with spread to the gastrointestinal tract and need revision. Major intraabdominal contamination that will put the anastomosis in jeopardy or critically ill patients who will not be able to tolerate a longer anesthesia may be contraindications for using the Santulli enterostomy procedure. Recently, the Santulli procedure was utilized effectively in symptomatic children with immature ganglion cells proven by full-thickness pathological biopsy.  

References:
1- Vanamo K, Rintala R, Lindahl H: The Santulli enterostomy in necrotising enterocolitis. Pediatr Surg Int. 20(9):692-4, 2004
2- Anadol AZ, Topgul K: Santulli enterostomy revisited: indications in adults. World J Surg. 30(10):1935-8, 2006
3- Tepetes K, Liakou P, Balogiannis I: The use of the Santulli enterostomy. World J Surg. 31(6):1343-4, 2007
4- Askarpour S, Ayatipour A, Peyvasteh M, Javaherizadeh H: A comparative study between Santulli ileostomy and loop ileostomy in neonates with meconium ileus. Arq Bras Cir Dig. 2020 33(3):e1538, 2020
5- Vinit N, Rousseau V, Broch A, et al: Santulli Procedure Revisited in Congenital Intestinal Malformations and Postnatal Intestinal Injuries: preliminary Report of Experience. Children 9:84, 2022. https://doi.org/10.3390/children9010084.
6- Lin Z, Liu M, Yan L, et al: Outcome of Santulli enterostomy in patients with immaturity of ganglia: single institutional experience from a case series. BMC Surg. 18;22(1):400, 2022

Hirschsprung's Disease and IBD

Hirschsprung's disease (HD) results from the absence of ganglion cell in the distal bowel described most commonly as classic if the rectosigmoid is affected to total colonic aganglionosis in very few cases (10%). Most diagnostic work-up and removal of aganglionic segment with pull-through reconstruction in children with HD is undertaken within the first year of life. Following surgical correction of HD some children (5-42%) develop an associated enterocolitis (HAEC) characterized by intestinal inflammation resulting in abdominal distension, fever, diarrhea, and sepsis. Inflammatory bowel disease (IBD) refers to describe conditions such as Crohn disease and ulcerative colitis causing symptoms that include diarrhea, pain, obstruction, weight loss, bloody stool, and fistula formation. Several reported cases have raised the possibility that HD and IBD may coexist, having a similar etiology and representing a spectrum of intestinal inflammatory disease in children. HAEC and IBD have similar clinical presentation including diarrhea, hematochezia, and abdominal pain. Both conditions are characterized by an abnormal intestinal mucosal barrier function. Less than 100 children with HD associated with IBD have been reported. Mean age at diagnosis of IBD was 7.7 years, most were males (73%), long-segment disease and total colonic aganglionosis predominated in 86% of all patients, with Duhamel procedure leading the cases (84%). Most IBD cases associated with HD were Crohn disease. An increasing length of aganglionosis is associated with a higher risk of HAEC. Individuals with HD have an increased risk to be diagnosed with IBD later in life, though the underlying cause is unknown. In Canada, being diagnosed with HD resulted in a 12-fold increased risk of subsequently being diagnosed with IBD. Persons with IBD were 24-40 times more likely to have had HD than matched control. Age at IBD onset is similar in individuals with HD and the general population with a median age of 21 years. The diagnosis of IBD in children with HD is difficult to confirm resulting in a delay. Crohn disease is the most common subtype of IBD found within this association. HD is more common in persons with trisomy 21, and trisomy 21 is a risk factor for developing HAEC. Trisomy 21 is not typically associated with IBD. IBD can emerge in more than 2% of children with HD and is more frequently classified as Crohn's disease than ulcerative colitis. Post-HD IBD is 3-fold more common in males. Management of IBD in these children is surgical in 30% and medical in the rest. Medical management include a combination of biologic agents (infliximab), methotrexate and steroids with mixed results. Genetics studies have identified nine hub genes associated with the co-occurrence of HD and Crohn disease. Among these genes, CXCL10 secreted by immune and non-immune cells is significantly higher in the Crohn disease and aganglionic segment of HD. Targeting CXCL10 could be an attractive approach to managing IBD. CXCL10 can be a potential biomarker for the development of Crohn disease in HD patients. These hub genes and diagnostic models will be beneficial to the prevention and diagnosis of postoperative concurrent Crohn disease after HD and provide a theoretical basis for the molecular mechanism of HD and Crohn disease co-occurrence.        

References:
1- Nakamura H, Lim T, Puri P. Inflammatory bowel disease in patients with Hirschsprung's disease: a systematic review and meta-analysis. Pediatr Surg Int. 34(2):149-154, 2018
2- Gosain A, Frykman PK, Cowles RA, et al: American Pediatric Surgical Association Hirschsprung Disease Interest Group. Guidelines for the diagnosis and management of Hirschsprung- associated enterocolitis. Pediatr Surg Int. 33(5):517-521, 2017
3- Granstrom AL, Amin L, Arnell H, Wester T. Increased Risk of Inflammatory Bowel Disease in a Population-based Cohort Study of Patients With Hirschsprung Disease. J Pediatr Gastroenterol Nutr. 66(3):398-401, 2018
4- Wolfson S, Whitfield Van Buren K. Very Early Onset of Inflammatory Bowel Disease in a Patient With Long-Segment Hirschsprung's Disease. ACG Case Rep J. 20;7(3):e00353, 2020. doi: 10.14309/crj.0000000000000353.
5- Granstrom AL, Ludvigsson JF, Wester T. Clinical characteristics and validation of diagnosis in individuals with Hirschsprung disease and inflammatory bowel disease. J Pediatr Surg. 56(10):1799-1802, 2021
6- Bernstein CN, Kuenzig ME, Coward S, et al: Increased Incidence of Inflammatory Bowel Disease After Hirschsprung Disease: A Population-based Cohort Study. J Pediatr. 233:98-104.e2, 2021 doi: 10.1016/j.jpeds.2021.01.060.
7- Wang J, Li Z, Xiao J, et al: Identification and validation of the common pathogenesis and hub biomarkers in Hirschsprung disease complicated with Crohn's disease. Front Immunol. 13:961217, 2022. doi: 10.3389/fimmu.2022.961217.

PSU Volume 60 No 03 MARCH 2023

Hereditary Multiple Intestinal Atresia

Intestinal atresia is the most common cause of congenital bowel obstruction in newborns with an incidence of one in 1500 live births. Approximately one third of all cases of neonatal bowel obstruction are due to intestinal atresia which can be sporadic most commonly or hereditary with a possible autosomal recessive mode of inheritance. Intestinal atresia are caused by an intrauterine mesenteric vascular accident occurring after the embryonic stage where blood fails to irrigate some segment of bowel causing a membrane (Type I), fibrous cord (Type II) or with complete disappearance of a substantial length of the intestine. The proportion of children with multiple jejunoileal atresia varies from 6-32%, with hereditary multiple intestinal atresia (HMIA) first reported in 1956 as the rarest form of multiple bowel atresia. HMIA is an unusual form of intestinal atresia with possible autosomal recessive mode of inheritance. Immune defects have been described in several patients with various types of familial bowel atresia. The combination of HMIA and immunodeficiency is invariably fatal. The immune deficiency affects T- and B-cell functions with lymphopenia, agammaglobulinemia and impaired mitogen responses. HMIA maintains a 100% lethality rate from continued postoperative intestinal failure and an associated severe immunodeficiency that has been increasingly recognized with this disorder. The association of HMIA with immunodeficiency affect multiple organs such as intestine, thymus, lungs, spleen, and liver. Newborns born with HMIA show symptoms of intestinal obstruction at birth and radiopaque shadows on abdominal plain films. Presenting symptoms include bilious vomiting, abdominal distension, and failure to pass meconium. The abdominal films show signs of gastric or duodenal atresia such as single or double bubble combined with typical large rounded or oval homogenous calcifications in the abdominal cavity. The excessive dilatation of the stomach, the presence of intraluminal calcifications and the conformation of rectal atresia by contrast enema is considered pathognomonic of HMIA. The intraoperative findings demonstrate widespread multiple atresia exclusively type I and II extending from the stomach to the rectum. Multiple webs, both occlusive and non-occlusive, and atretic cords are found throughout the small intestine. No mesenteric defect as in Type IIIa or IIIb is identified. There is necrotic nonbilious calcified material within the lumen of the bowel and the intestinal mucosa appeared atrophic. The entire or part of the colon except for the ileocecal valve is a continuation of string-like solid fibrous cord extending to the distal rectum. There could be cystic dilatation of the bile ducts in some cases with both complete pyloric and duodenal or proximal jejunal atresia. The pathogenesis is still speculative though a combined immunodeficiency should be excluded. A fatal outcome occurs in most cases. Antenatally polyhydramnios is the presenting feature of HMIA in 20-35% of cases and is more frequently associated with proximal bowel obstruction. Prenatal ultrasound can raise suspicion of HMIA in the presence of polyhydramnios, gastric dilatation, intraluminal calcifications and thickened echogenic wall. Fetal MRI findings particularly those of simultaneous pyloric and intestinal obstructions with numerous dilated bowel loops suggest the diagnosis. The aim of surgical intervention is to restore continuity of the gastrointestinal tract and maintain maximum length of viable bowel. An autosomal recessive transmission has been proposed as a probable explanation of this disease. Through whole exome sequencing of patients with HMIA, two mutations in a single gene, the tetratricopeptide repeat domain 7A gene TTC7A could explain the disease in the affected cases. Mutation in TTC7A is often associated with severe intestinal defects and severe combined immunodeficiency and inflammatory bowel disease. HMIA associated with a TTC7A mutational defect is characterized by multiorgan impairments. After operative repair babies with HMIA continue to have poor gastrointestinal function even if enough intestinal length is preserved to avoid the classic short gut syndrome. The outcome of HMIA depends upon the length and regions of bowel involved. The degree of postoperative short bowel syndrome is a major determinant of survival. The most common cause of death is infection related to pneumonia, peritonitis, and sepsis. The family should be aware of the dimmed prognosis.

References:
1- Bilodeau A, Prasil P, Cloutier R, et al: Hereditary multiple intestinal atresia: thirty years later. J Pediatr Surg. 39(5):726-30, 2004
2- Ali YA, Rahman S, Bhat V, Al Thani S, Ismail A, Bassiouny I: Hereditary multiple intestinal atresia (HMIA) with severe combined immunodeficiency (SCID): a case report of two siblings and review of the literature on MIA, HMIA and HMIA with immunodeficiency over the last 50 years. BMJ Case Rep. 2011 Feb 9;2011:bcr0520103031. doi: 10.1136/bcr.05.2010.3031.
3- Samuels ME, Majewski J, Alirezaie N, et al: Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. J Med Genet. 50(5):324-9, 2013
4- Githu T, Merrow AC, Lee JK, Garrison AP, Brown RL: Fetal MRI of hereditary multiple intestinal atresia with postnatal correlation. Pediatr Radiol. 44(3):349-54, 2014
5- Fernandez I, Patey N, Marchand V, et al: Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort. Medicine (Baltimore). 93(29):e327, 2014
6- Al-Zaiem MM, Alsamli RS, Alsulami EA, Mohammed RF, Almatrafi MI: Hereditary Multiple Intestinal Atresia: A Case Report and Review of the Literature. Cureus. 2022 Oct 30;14(10):e30870. doi: 10.7759/cureus.30870. 2022

Commotio Cordis

Commotio Cordis (CC) is a life-threatening dysrhythmia produce by a direct nonpenetrating low impact blow to the chest. It is defined as sudden cardiac arrest in the absence of apparent structural heart disease after nonpenetrating chest injury. Most cases of commotio cordis occurs in young patients, specifically boys who are younger that 16 years, with almost three-fourth of cases occurring after some type of sport participation such as baseball, hockey, lacrosse, or softball. The other third occurs out of sport activities including intentional chest blows due to fighting, child abuse, or impact from snowballs or hollow plastic toys. In infants commotio cordis occurs in the setting of child abuse. CC is one of the most common causes of sudden cardiac death in athletes, with hypertrophic cardiomyopathy being the most common. CC is characterized as a sudden disturbance of cardiac rhythm in the absence of demonstrable signs of significant mechanical injury to the heart induce by a direct blow to the chest. A structural injury is not a contributing aspect to the pathogenesis of the often-lethal rhythm disturbance seen in CC. In terms of the rhythm disturbance created, CC most commonly is limited to the sudden onset of ventricular fibrillation, though it may also manifest as other cardiac rhythm disturbances such as heart block, ventricular tachycardia, bundle branch block, ST-T wave abnormalities or asystole. It has been demonstrated experimentally that blow over the center of the heart are more likely to cause a ventricular fibrillation than at any other location and is associated to peak elevations of the left ventricular pressure. Coronary vasospasm may also play a role in some cases of CC. The occurrence of CC is thought to require the rare confluence of a blow over the heart and precise timing during the vulnerable phase of repolarization (10-30 milliseconds prior to the peak of the T-wave). The sudden blow causes a dramatic increase in left ventricular intracavitary pressure resulting in increased stretching of cell membranes and activation of an increase potassium ion concentration current across the cell membranes of the myocytes. Higher energy impacts are more likely to cause ventricular fibrillation compared to low velocity impacts. Collapse is instantaneous or within a few seconds. Early resuscitation seems to be the most important predictor for successful recovery including beginning therapy with standard cardiopulmonary resuscitation protocols.  The rapid use of an automated defibrillator is the optimal approach and should be used wherever possible before transport to a health care facility. Early initiation of CPR, followed by early defibrillation in less than 4 to 8 minutes from time of collapse has the greatest impact on successful resuscitation. Survival rates has increased steadily over the years and recent survival is now greater than 65%. Any child who has experienced syncope during sport activities should not be allowed to return to the game. If an automated external defibrillator was utilized for resuscitation of a CC event, the computer disc storage system should be secured and studied to document the rhythm disturbance at the time of the shock. Once the child is transported to the hospital several therapeutic maneuvers are critical and related to the length of the cardiac arrest. Mortality and risk of hypoxic permanent brain injury is high during commotio cordis events. Cardiac reassessment and evaluation is recommended before the patients resumes sports activities. To assess the degree of injury continuous cardiac monitoring, ventilatory support, chest films and electrocardiogram with echocardiogram should be performed. Blood chemistry including levels of calcium, magnesium, and cardiac enzymes (serial troponin and creatine kinase) should be obtained. ICU monitoring with cardiac telemetry should be performed in the first 24 hours and subsequently as needed. Syncope can mimic CC but is usually not associated with impact to the chest wall. With CC the possibility of recurrence is so small that some physicians recommend return to participation after exercise stress test has normalized. CC is a survivable phenomenon. As a measure of prophylaxis, schools, universities, and municipal parks have implemented automated external defibrillators program where staff is trained in their use and one or more devices are placed in areas accessible to any athletic event. CC prognosis depends on the rapid identification of the event and availability of cardiac defibrillators in site.  

References:
1- Zangwill SD, Strasburger JF. Commotio cordis. Pediatr Clin North Am. 51(5):1347-54, 2004
2-  Link MS. Pathophysiology, prevention, and treatment of commotio cordis. Curr Cardiol Rep. 16(6):495, 2014
3- Link MS, Estes NAM 3rd, Maron BJ. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 13: Commotio Cordis: A Scientific Statement From the American Heart Association and American College of Cardiology. J Am Coll Cardiol. 66(21):2439-2443, 2015
4- Davey BT, Quintana C, Upadhyay S. An Unusual Case of Commotio Cordis Resulting in Ventricular Flutter. J Emerg Trauma Shock. 11(3):225-227, 2018
5- Nazer D, Kannikeswaran N, Schmidt C. Commotio cordis: A case report of a fatal blow. J Forensic Sci. 67(1):384-386, 2022
6- Bruera MJ, Pierola Guardia DA, Sotelo Ledezma E, Blanco AC. Commotio cordis (cardiac concussion) in a child. A case report. Arch Argent Pediatr. 2022 Nov 3:e202202593. English, Spanish. doi: 10.5546/aap.2022-02593.eng.

Priapism

Priapism refers to a prolonged full or partial penile erection which last more than four hours not related to sexual activity or stimulus. Priapism is a urological emergency and the treatment of priapism aims to avoid penile disfigurement or shortening, erectile dysfunction and psychological sequelae. Priapism of the clitoris can occur and is called clitorism. Though rare, priapism does occurs in the pediatric age. There are three widely accepted types of priapisms: 1) ischemic priapism which is a low-flow veno-occlusive disease caused by blocked venous outflow that prevents oxygenated arterial blood from perfusing the corpora cavernosa; 2) stuttering priapism which refers to intermittent and recurrent ischemic, and 3) non-ischemic due to high flow arterial etiology. A fourth type is that which occurs in neonates. Ischemic priapism is the most common type seen in children, typically painful. Sexual activity and nocturnal erections are precipitators. The corpora cavernosa is markedly rigid, while the glans and corpora spongiosa is flaccid. A compartment syndrome within the tunica albuginea occurs due to elevated interstitial pressure causing microvascular compromise and ischemia. The lack of arterial inflow creates a hypoxic environment that damages the smooth muscle tissue leading to irreversible necrosis and fibrosis. Stuttering priapism is a recurrent unwanted painful erection, often self-limited, but may precede an ischemic priapism. It is trigger by nocturnal erections and is associated with sickle cell disease. Stuttering priapism causes recurrent  visits to the emergency department, sleep deprivation, embarrassment and sexual performance anxiety. Each episode carries a risk of fibrotic damage to the corpora cavernosa if untreated.  The non-ischemic priapism variety is a partial erection due to unregulated cavernous arterial inflow which is usually painless. Piesis sign consisting of perineal compression that results in penile detumescence but recurs after removal of the pressure strongly suggest non-ischemic priapism in children. A history of blunt trauma to the penis or an iatrogenic needle injury is most commonly described etiology. The result is a disruption of the cavernous arterial anatomy creating an arteriolar-sinusoidal fistula. This type might not require emergency urological treatment. Neonatal priapism is a prolonged erection lasting more than four hours during the first month of life, it usually occurs in the first few days of life and might persist for 2-12 days with an average of 5 days. The incidence of priapism is almost one for every 100,000 males per year, most frequently during the fifth decade of life. Sickle cell disease (SCD)  is the most common cause of priapism in children with most cases of the stuttering variety. Mean episode is at age 15. The tumescence of priapism is initiated by relaxation of the cavernous arteries and sinusoidal smooth muscle. This increases the arterial inflow and capacitance. Sinusoids trap blood, tumescence occurs and the tunica albuginea is stretched occluding emissary veins. Contraction of the ischiocavernous muscle increases the cavernosal pressure exceeding systolic blood pressure. Nitric oxide synthetase is produced increasing nitric oxide and acting on both cavernosa artery and sinusoidal smooth muscle elevating c GMP promoting smooth relaxation. In cases of SCD deoxygenated hemoglobin S causes sickling and microvascular obstruction stimulating hemolysis and increasing free hemoglobin levels which deactivate nitric oxide causing ischemic priapism. Nocturnal erections, sexual activity, dehydration, fever and exposure to cold are the most common precipitants of priapism in children with SCD. Childhood leukemias can also cause priapism. Penile, perineal or pelvic trauma such as straddle or coital injury are the commonest cause of non-ischemic priapism. In neonatal priapism the cause is unknown but subclinical birth trauma is hypothesized to cause most cases. Priapism can also be caused by drugs such as PDE-5 inhibitors, testosterone and anti-psychotics. First evaluation to differentiate ischemic priapism from non-ischemic priapism is by using penile Doppler US. Management depends on the type of priapism the child develops. Opiates analgesia is usually require in ischemic priapism. Cold packs are analgesic and may cause  vasoconstriction decreasing penile blood flow. Hemoglobinopathy and leukemia must be rule out. Successful aspiration and irrigation is reported under conscious sedation with local anesthesia in 4-18 years old. Ketamine is an established detumescence agent and may resolve priapism. During aspiration the presence of dark deoxygenated blood confirms the diagnosis of ischemic priapism and the corpora should be immediate decompressed until bright blood appears. During aspiration and irrigation sympathomimetics (phenylephrine) might be used. If repeated sympathomimetic is unsuccessful a surgical fistula should be formed. In SCD induced priapism hyperhydration, oxygen therapy, analgesia and exchange transfusions might be needed. For leukemia induced priapism antileukemic therapy (chemotherapy/leukophoresis) and anticoagulation has been advocated. In refractory cases superselective embolization of the internal pudendal artery  might be needed. Most hematologic induced priapism in children can be managed with conservative therapy including oxygenation, intravenous hydration and minimally-invasive procedure such as corporal aspiration irrigation and injections.             

References:
1- Donaldson JF, Rees RW, Steinbrecher HA: Priapism in children: a comprehensive review and clinical guideline. J Pediatr Urol. 10(1):11-24, 2014
2- Wang HH, Herbst KW, Rothman JA, Shah NR, Wiener JS, Routh JC: Trends in Sickle Cell Disease-related Priapism in U.S. Children's Hospitals. Urology. 89:118-22, 2016
3- Liguori G, Rizzo M, Boschian R, et al:The management of stuttering priapism. Minerva Urol Nefrol. ;72(2):173-186, 2020
4- Sarrio-Sanz P, Martinez-Cayuelas L, March-Villalba JA, et al: High-flow priapism in pediatric population: Case series and review of the literature. Actas Urol Esp (Engl Ed). 45(9):597-603, 2021
5- Akgul AK, Ucar M, Ozcakir E, Balkan E, Kilic N: Rare emergency in children: Priapism and stepwise treatment approach. Ulus Travma Acil Cerrahi Derg. 28(4):464-470, 2022
6- Patel SR, Reddy A, Dai M, Passoni N, Khera M, Koh CJ: Is urgent surgical management necessary for priapism in pediatric patients with hematologic conditions? J Pediatr Urol. 18(4):528.e1-528.e6, 2022

PSU Volume 60 No 04 APRIL 2023

CDH: Lung to Head Ratio

Congenital diaphragmatic hernia (CDH) is a birth defect associated with a high mortality due to lung hypoplasia and pulmonary hypertension. A defect in the diaphragm allows the abdominal organs to herniate toward the thoracic cavity leading to compression of the lungs, abnormal lung development, with pulmonary hypoplasia and persistent pulmonary hypertension after birth. The diagnosis can be made with prenatal ultrasound early in pregnancy. Pulmonary hypertension is a common cause of mortality and morbidity among survivors of CDH. The presence of pulmonary hypertension in infants with CDH is due to decreased pulmonary arterial density and abnormal arborization leading to a significant reduced distal cross-sectional vascular area. The lung-to-head ratio (LHR) is a prenatal prognostic indicator for CDH. The LHR as measured by prenatal ultrasound is the ratio of the area of the lung contralateral to the hernia defect to the fetal biparietal head circumference. The area of the lung is measured at the level of the four-chamber view of the fetal heart and is defined as the product of the longest two perpendicular transverse diameters in milliliters. The LHR is then calculated as a simple ratio of lung area (in square millimeters) to head circumference (in milliliter) ideally between 24 and 28 weeks of gestation. LHR enables an indirect assessment of the contralateral fetal lung volume. LHR has been suggested as a way to estimate the degree of pulmonary hypoplasia and predict outcomes in children born with CDH. Lower LHR is associated with increased mortality and needs of use of ECMO. A threshold LHR of 0.85 predicts mortality with 95% sensitivity and 64% specificity. There are few long-term survivors in infants with an LHR < 1.0. Prenatal markers identified to help predict perinatal outcomes in children with left-sided CDH include low LHR, liver position, intrathoracic position of the stomach, mediastinal shifts, polyhydramnios, and early diagnosis before 25 weeksÕ gestation. Prenatal prediction of survival in CDH relies mostly on indirect measurement of fetal lung volumes providing physicians with insight into the potential severity of postnatal pulmonary deficits and helping select appropriate therapeutic interventions including prenatal surgical intervention. Serial ultrasound evaluation of fetuses with CDH have demonstrated increasing LHR values in survivors as gestational age advances, while in non-survivors there is no apparent increase in the LHR throughout gestation. During normal fetal development the LHR increases over the course of gestation in babies not affected by CDH because the pulmonary area increases four times more than the cephalic circumferences. This means that the LHR takes gestational age into account. The observed to expected US lung-to-head ratio express the measured lung-to-head ratio as a centile of the normal median to gestational age. Similarly, the fetal lung volume measured by MRI and expressed as a percentage of the expected fetal lung volume for gestational age has a prognostic predictive value. The LHR and fetal lung volume predict survival, need for ECMO and development of chronic lung disease in fetuses with left-sided CDH. The correlation does not reach statistical significance at any time of gestation for cases with right-sided CDH. Long term outcomes regarding neurological development, musculoskeletal development, and nutritional status in moderate to severe CDH are not predicted by measurement in LHR. Quantification of the extent of liver tissue herniation in right sided CDH by US or MRI or position of the stomach in the thorax are more predictive for survival, even independent of the LTH ratio. In isolated left sided CDH patients the LTH predicts survival and development of chronic lung disease in survivors in an era of standardized neonatal treatment protocol.       

References:
1- Garcia AV, Fingeret AL, Thirumoorthi AS, et al: Lung to head ratio in infants with congenital diaphragmatic hernia does not predict long term pulmonary hypertension.  J Pediatr Surg. 48(1):154-7, 2013
2- Partridge EA, Peranteau WH, Herkert L, et al: Rate of increase of lung-to-head ratio over the course of gestation is predictive of survival in left-sided congenital diaphragmatic hernia. J Pediatr Surg. 51(5):703-5, 2016
3- Kastenholz KE, Weis M, Hagelstein C, et al: Correlation of Observed-to-Expected MRI Fetal Lung Volume and Ultrasound Lung-to-Head Ratio at Different Gestational Times in Fetuses With Congenital Diaphragmatic Hernia. AJR Am J Roentgenol. 206(4):856-66, 2016
4- King SK, Alfaraj M, Gaiteiro R, et al: Congenital diaphragmatic hernia: Observed/expected lung-to-head ratio as a predictor of long-term morbidity. J Pediatr Surg. 51(5):699-702, 2016
5- Snoek KG, Peters NCJ, van Rosmalen J, et al: The validity of the observed-to-expected lung-to-head ratio in congenital diaphragmatic hernia in an era of standardized neonatal treatment; a multicenter study. Prenat Diagn. 37(7):658-665, 2017
6- Senat MV, Bouchghoul H, Stirnemann J, et al: Prognosis of isolated congenital diaphragmatic hernia using lung-area-to-head-circumference ratio: variability across centers in a national perinatal network. Ultrasound Obstet Gynecol. 51(2):208-213, 2018

Distal Intestinal Obstruction Syndrome

Distal intestinal obstruction syndrome (DIOS) is a common and characteristic complication of children with cystic fibrosis (CF). CF is an autosomal recessive disease characterized by exocrine pancreatic insufficiency and progressive pulmonary disease. CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator gene which encodes a protein whose main function is to regulate chloride ion transport. DIOS is characterized by the accumulation of viscid fecal material within the lumen of the bowel combined with sticky mucoid material intestinal content adherent to the intestinal wall affecting the terminal ileum and cecum. This fecal material connects strongly with the crypts and villi being very difficult to remove. Intermittently the child with DIOS due to cystic fibrosis develops bowel obstruction. The clinical presentation can be acute, or chronic with intermittent abdominal pain associated with abdominal distension and vomiting. Occurrence of DIOS is related to the severity of the CF genotype. DIOS affects between 10-22% of individuals with CF. Adults are more commonly affected than children by DIOS. DIOS affected children have a right lower quadrant mass which is usually palpable and can be seen as fecal material in plain abdominal films.  DIOS is defined a complete or incomplete bowel obstruction with fecal mass in the ileocecum. In CF defective cystic fibrosis transmembrane conductance regulator function leads to reduced chloride and fluid secretion in the intestinal epithelium and airway. Absence of this gene leads to thickened, dehydrated mucus. Besides, gut transit is prolonged in CF affecting gastric emptying and ileal-colonic transit. Poorly controlled fat absorption contributes to DIOS by altering the viscosity of luminal content. Most children with DIOS are pancreatic insufficient. Previous history of meconium ileus is also a strong risk factor for developing DIOS later in life. Poorly controlled fat malabsorption is frequently reported in DIOS patients. Risk of DIOS increases after lung transplantation. Clinically DIOS is associated with right lower quadrant colicky abdominal pain, nausea, bilious vomiting, and fluid levels. Abdominal CT with contrast can established the diagnosis in the proper setting of a child suffering from CF. CT-scan shows significant proximal small bowel dilatation with inspissated fecal material in the distal ileum. Appendicitis, chronic constipation, and intussusception can mimic DIOS. The clinical presentation of fibrosing colonopathy may be quite similar to DIOS with abdominal pain, distension, vomiting and constipation. Management of DIOS is empirical. Patient with incomplete DIOS respond to oral rehydration combined with stool softeners which contain an osmotic laxative containing polyethylene glycol (golyte). It can be given at a dose of 20-40 ml/kg/hr. up to a maximum of 1L/hr. over 8 hours. The aim of management is to achieve fecal effluent consistent of clear fluid and resolution of pain, abdominal distension, and vomiting. Alternative Gastrograffin can be administered orally or by nasogastric tube at a dose of 50-100 ml in 200 ml of water or juice depending on the age of the child. The use of N-acetyl cysteine administered orally can also be used effectively. N-acetylcysteine exhibits a mucolytic action through its free sulfhydryl group which opens the disulfide bonds in mucoproteins to lower mucous viscosity. It can be given enterally by mouth or feeding tube and also rectally. It may be more effective in relieving incomplete obstruction than complete obstructions. Gastrograffin can be used as a hydrostatic enema retrograde lavage so as to reach the small distal bowel fecal material. Lactulose an oral osmotic laxative is widely used but may cause flatulence or abdominal pain in high doses. Surgery is seldom required and is reserved for the most refractory cases nor responding to medical management. As prophylaxis maintenance laxative therapy should be continued avoiding dehydration and providing adequate pancreatic enzyme dosage.  

References:
1- Colombo C, Ellemunter H, Houwen R, Munck a, Taylor C, Wilschanski M; ECFS: Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients.  J Cyst Fibros. 10 Suppl 2:S24-8, 2011
2- Schauble AL, Bisaccia EK, Lee G, Nasr SZ: N-acetylcysteine for Management of Distal Intestinal Obstruction Syndrome. J Pediatr Pharmacol Ther. 24(5):390-397, 2019
3- Sandy NS, Massabki LHP, Gonsalves AC, et al: Distal intestinal obstruction syndrome: a diagnostic and therapeutic challenge in cystic fibrosis. J Pediatr (Rio J). 96(6):732-740, 2020
4- Gilchrist FJ, Green J, Carroll W: Interventions for treating distal intestinal obstruction syndrome (DIOS) in cystic fibrosis. Cochrane Database Syst Rev. 12(12):CD012798, 2021
5- Carroll W, Green J, Gilchrist FJ: Interventions for preventing distal intestinal obstruction syndrome (DIOS) in cystic fibrosis. Cochrane Database Syst Rev. 12(12):CD012619, 2021
6- Sohail Z, Bin Waris W, Sheikh NI: Distal Intestinal Obstruction Syndrome Relieved by Ileoscopy in a Patient With Cystic Fibrosis: A Case Report and Literature Review. Cureus. 14(8):e28486, 2022

Propofol Infusion Syndrome

Propofol is a very common sedative used in anesthesia and surgery. Propofol has many pharmacological advantages over other anesthesia agents such as rapid effect, short action, and fewer side effects like postoperative nausea. Pediatric use of propofol includes induction and maintenance of general anesthesia as well as sedation during non-surgical intervention and ICU care. Propofol exerts its hypnotic actions by activation of the central inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Propofol infusion syndrome (PIS) is defined as the occurrence of acute bradycardia resistant to treatment and progressing to asystole associated with propofol infusion. The bradycardia is combined with one of the following: 1) lipemic plasma, fatty liver enlargement; 2) metabolic acidosis with negative base excess less than 10 mM, and 3) rhabdomyolysis or myoglobinuria. The primary feature of PIS is metabolic acidosis (most common feature), ECG changes and rhabdomyolysis. PIS can lead to cardiac and renal failure. The child can develop symptoms and signs of lactic acidosis, hypotension, renal, cardiac, and circulatory failure, oliguria, rhabdomyolysis, elevated CK, serum urea and serum potassium, with lipemic plasma, liver enlargement, ketonuria, increased liver tests and red colored urine. Risk factors identified include airway infection, poor oxygen delivery, sepsis, serious head injury and high-dose (> 5 mg/kg/hr) long-term propofol sedation for more than 48 hours, associated with increased catecholamines and glucocorticoid serum levels. Lipemia due to failure of hepatic lipid regulation leads to sequestration of propofol into the lipid phase leading to lowered free propofol levels and insensitivity to propofol. Mortality is more common in children below 19 years of age, males and those receiving vasopressors in the ICU. The syndrome can be associated with a right bundle branch block in the EKG. PIS occurs with the use of high doses of propofol for prolonged periods of time. Pathological findings in PIS include cytolysis of skeletal and cardiac muscle. Free fatty acids are a pro-arrhythmic risk factor in PIS. Is theorized that an hereditary fatty acid metabolism impairment resembling medium-chain acyl-CoA dehydrogenase deficiency is responsible for the susceptibility of developing PIS. Propofol impedes the electron flow through the respiratory chain and coenzyme Q is the main site of interaction with propofol interfering with mitochondrial energy production. Low carbohydrate supply is a risk factor for PIS due to energy demand which is satisfied by lipolysis when carbohydrates are low. PIS has no definitive diagnostic test; early detection is highly crucial for initiating early treatment. Management of PIS include stopping immediately the infusion of propofol. Hemodynamic stabilization should be achieved along with carbohydrate substitution. Hemodialysis or hemofiltration is recommended for elimination of propofol and toxic metabolites. Extracorporeal membrane oxygenation has also been reported as beneficial in some cases. Propofol is not approved for sedation in some pediatric intensive care unitÕs patients. A dose limit of 4 mg/kg/hr. is recommended for sedation of adult patients and a period of seven days should not be exceeded, preferably not more than 48 hours. Acid base metabolism and CK should be monitored during propofol infusion use. Total intravenous anesthesia with propofol is regarded as a safe procedure with few side effects in pediatric patients and is considered a standard procedure. Alternatives for propofol use include dexmedetomidine or midazolam.

References:
1- Fudickar A, Bein B: Propofol infusion syndrome: update of clinical manifestation and pathophysiology. Minerva Anestesiol. 75(5):339-44, 2009
2- Vanlander AV, Okun JG, de Jaeger A, et al: Possible pathogenic mechanism of propofol infusion syndrome involves coenzyme q. Anesthesiology. 122(2):343-52, 2015
3- Chidambaran V, Costandi A, D'Mello A: Propofol: a review of its role in pediatric anesthesia and sedation. CNS Drugs. 29(7):543-63, 2015
4- Hemphill S, McMenamin L, Bellamy MC, Hopkins PM: Propofol infusion syndrome: a structured literature review and analysis of published case reports. Br J Anaesth. 122(4):448-459, 2019
5- Ichikawa T, Okuyama K, Kamata K, Masui K, Ozaki M: Suspected propofol infusion syndrome during normal targeted propofol concentration. J Anesth. 34(4):619-623, 2020

PSU Volume 60 No 05 MAY 2023

Meconium Obstruction of Prematurity

Meconium obstruction of prematurity (MOP) is an specific type of meconium obstruction described in premature neonates with very low birth weight (< 1500 g) or extremely low birthweight (< 1000 g). This obstruction occurs in infants with particular risk factors, affects the ileum and colon, and is not associated with cystic fibrosis. Ileal obstruction by meconium in premature, low birth weight babies is a distinct clinical entity. MOP is caused by inspissated meconium in the colon and/or terminal ileum resulting in mechanical bowel obstruction. The etiology is thought to be a combination of the highly viscid meconium of prematurity and the poor motility of the premature bowel. Delayed maturity of interstitial cells of Cajal has been suggested as a cause of distal ileal meconium obstruction combined with increased viscosity of exocrine secretions.  This condition is not related to mucoviscidosis or Hirschsprung's disease and is commonly seen in extremely low-birth weight infants. MOP is similar to meconium plug syndrome or small left colon syndrome. Guidelines for the diagnosis of MOP in low-birth weight babies include the following characteristics: 1) severe prematurity and low birth weight; 2) presence of at least one risk factor such as high-risk pregnancy, maternal diabetes, cesarean delivery, or maternal magnesium sulfate administration (magnesium depress smooth muscle cells of the bowel); 3) low-grade obstruction; 4) benign systemic and abdominal examination; and 5) distended loops of bowel without air-fluid levels. A contrast colon study is not essential to establish the diagnosis unless there is therapeutic intent. Likewise testing for cystic fibrosis is not indicated. The presentation of this disorder occurs around 10-14 days of life and involves abdominal distension, bile-stained vomiting, and intestinal perforation. MOP is very severe in extremely low births infants where their bowel can perforate easily. Plain X-rays film of the abdomen shows multiple dilated loops of bowel without pneumatosis and without air-fluid level. The diagnosis may only be confirmed by intervention resulting in the passage of meconium plugs or by contrast radiology. The goal of treatment is to evacuate the tenacious meconium by stimulating peristalsis and reducing its viscosity. Once the obstruction is release there will be no recurrence. In extremely premature infants with delayed passage of meconium glycerin suppositories or saline irrigation are regularly utilized in the NICU to help evacuate meconium. Initial management of MOP includes using a diluted Gastrograffin enema which is diagnostic, therapeutic and the gold standard. The higher osmolarity of Gastrograffin and need of radiological suite transport to small babies has been questioned. If the contrast successfully refluxes through the ileocecal valve the distal ileum can be seen full of impacted meconium. The success rate depends heavily on the extent of colon and ileum filling which is less in MOP as compared with mucoviscidosis from cystic fibrosis. When adding Tween-80 to the Gastrograffin enema it was more efficient, but this media might be toxic. Gastrograffin can be absorbed into the bloodstream causing tissue dehydration. Gastrograffin enema is inappropriate for hemodynamically unstable patients complicated with bowel obstruction. Iopamidol, a hydrophilic contrast medium used mainly for angiography is less invasive of capillary epithelial cells with an osmotic pressure of 300-600 mOsm which is significantly lower than Gastrograffin. If perforation or absorption into the bloodstream occurs, Iopamidol is less invasive. The procedure which is performed in the incubator using ultrasound guided hydrostatic enema has been utilized with good results. The failure rate of Iopamidol is associated with delaying management. Surgical intervention is considered for patients who develop rapid abdominal distension that is at risk of perforation. The procedure should consist of enterostomy, irrigation and manual evacuation of the impacted meconium. In cases of bowel perforation minimal resection and primary anastomosis is favored.

References:
1- Emil S, Nguyen T, Sills J, Padilla G: Meconium obstruction in extremely low-birth-weight neonates: guidelines for diagnosis and management.  J Pediatr Surg. 39(5):731-7, 2004
2- Nakaoka T, Shiokawa C, Nishihara M, Tamai H, Funato M, Uemura S: Iopamidol enema treatment for meconium obstruction of prematurity in extremely low-birth weight infants: a safe and effective method. Pediatr Surg Int. 25(3):273-6, 2009
3- Siddiqui MM, Drewett M, Burge DM: Meconium obstruction of prematurity. Arch Dis Child Fetal Neonatal Ed. 97(2):F147-50, 2012
4- Kim YJ, Kim EK, Kim ES, et al: Recognition, diagnosis and treatment of meconium obstruction in extremely low birth weight infants. Neonatology. 101(3):172-8, 2012
5- Nakaoka T, Nishimoto S, Tsukazaki Y, et al: Ultrasound-guided hydrostatic enema for meconium obstruction in extremely low birth weight infants: a preliminary report. Pediatr Surg Int. 33(9):1019-1022, 2017
6- Sung SI, Ahn SY, Choi SJ, et al: Increased Risk of Meconium-Related Ileus in Extremely Premature Infants Exposed to Antenatal Magnesium Sulfate. Neonatology. 119(1):68-76, 2022

Melanotic Neuroectodermal Tumor of Infancy

Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a very rare tumor found in infants mostly involving the bones of the jaw. There are around 500 cases reported worldwide, with most cases from USA followed by India, Germany, and Brazil. MNTI is a pigmented neoplasm which arises from neural crest cells. NMTI typically occurs in infants younger than one year of age with a slight male predilection. Many cases are associated with an increase of urinary vanillylmandelic acid secretion (40%). This tumor has many names, such as congenital melanocarcinoma, pigmented ameloblastoma, retinal anlage tumor, pigmented epulis, melanotic epithelial odontoma or melanotic progenome. Mean age of presentation is 4 to 5 months. A few congenital and prenatal cases have been reported. MNTI is a benign tumor which is locally aggressive with rapid onset and very fast growth rate. Infants presents with a rapidly growing, painless, firm non ulcerated mass with a blue or black discoloration (bluish pigmentation), affecting the craniofacial region in 90% of cases. The maxilla as the most common site of involvement followed by skull and mandible. The mean size for MNTI is 3.5 cm, but lesions can attain a size of 20 cm. Local invasion by the tumor can lead to bony destruction, tooth displacement, and feeding difficulties. Only 3% of these tumors are frankly malignant with just a few producing metastases. Metastatic spread has been documented to lymph nodes and the central nervous system. Extent of MNTI is performed with dental radiographies, CT-Scan and MRI, though imaging is seldom diagnostic and tissue biopsy is needed. On imaging the tumor presents as a well-demarcated radiolucent lytic lesion within bone that may have features concerning for local destruction. CT-Scan shows a hyperdense mass with bone remodeling and expansion. Pathology shows a characteristic biphasic cell distribution of large epithelioid melanogenic cells and small primitive neuroblastic cells with scattered melanin pigment. The diagnosis is further confirmed using immunohistological stains since both cell types are positive for vimentin and neuron-specific enolase. Immunohistochemical exam can reveal signs of possible aggressive growth behavior. The differential diagnosis of MNTI includes other small round blue cell tumors of childhood, especially neuroblastoma, Ewing sarcoma, alveolar rhabdomyosarcoma, malignant melanoma, and lymphoma. Management of MNTI consist of surgical excision with a 2-5 mm healthy margin of tissue during removal. Complete surgical excision is curative. Recurrences is due to multicentric growth and incomplete surgical excision. Recurrence can be fatal especially when involving the central nervous system or other vital structures. Predominance of a neuroblast-like component and an inconspicuous large cell component were also associated with an aggressive course and high risk of local recurrence. Infants receiving a diagnosis within the first 2 months of life were more likely to have recurrence within 6 months and a shorter disease-free survival. Infants with a diagnosis at age 4.5 months or older had minimal risk of recurrence. Neoadjuvant therapy (chemotherapy and/or radiotherapy) is usually reserved for inoperable tumors, involvement of the central nervous system and other vital structures, or when clear surgical margins are not obtainable. Due to the high recurrence rate of 15-27%, is imperative five year of follow-up.  

References:
1- Goswami M, Bhushan U, Mohanty S: Melanotic Neuroectodermal Tumor of Infancy. J Clin Diagn Res. 10(6):ZJ07-8, 2016
2- Soles BS, Wilson A, Lucas DR, Heider A: Melanotic Neuroectodermal Tumor of Infancy. Arch Pathol Lab Med. 142(11):1358-1363, 2018
3- Goel D, Qayoom S, Goel MM, Rawa J: Melanotic neuroectodermal tumor of infancy (MNTI) - A rare entity. J Cancer Res Ther. 18(3):784-787, 2022
4- Kumar KS, Naleer MH, Visweswaran V, Krishnamurthy G: Melanotic Neuroectodermal Tumor of Infancy: A Rare Case Report. Asian J Neurosurg. 17(1):131-133, 2022
5- de Sousa ALA, de Almeida WC, de Pinho Mendes J, Martins Montalli VA, Pinto ASB: Melanotic Neuroectodermal Tumor of Infancy: the Use of Immunohistochemical Analysis. Acta Stomatol Croat. 56(2):176-182, 2022

Gastric Pneumatosis

Pneumatosis intestinalis is the result of gas infiltrating into the wall of the bowel. It can be detected as a radiological finding, or intraoperatively as the result of an underlying pathological process. Gastric pneumatosis (GP), also known as interstitial emphysema of the stomach, is a rare and primarily radiological diagnosis that can occur in children and adults. It has been seen in preterm and term babies, along with infants up to one year of age. The condition can be noninfectious (gastric pneumatosis) or infectious (emphysematous gastritis). Gastric pneumatosis is caused by a disruption of the gastric mucosa, which results in air dissecting into the stomach wall. This disruption results in air dissecting into the stomach wall. Four mechanisms can be identified, often acting concurrently, including local or systemic hypoperfusion with gastric ischemia; spontaneous or iatrogenic disruption of the gastric mucosa; intramural infection by gas-producing organisms; and dissection of mediastinal air toward the stomach. In children this disruption typically results from gastric outlet obstruction caused by pyloric stenosis, duodenal atresia or stenosis, duodenal ulcers, malrotation, or tumors. It can also occur from protracted vomiting, instrumentation or tracking of air through the mediastinum or the pneumothorax. Pyloric stenosis is the most common cause of gastric pneumatosis in young infants. Pneumatosis of the stomach likely results from the increased intragastric pressure associated with pyloric hypertrophy and gastric outlet obstruction. The mechanical damage theory is the most common theory regarding the pathophysiology of gastric pneumatosis in infants. It involves proximal gastrointestinal obstruction typically at the pylorus or duodenum, leading to gastric dilatation and elevated gastric pressure. Chronically elevated gastric pressure accompanied by forceful vomiting causes transient pressure peaks leading to gastric mucosal tears which allows air to dissect into the submucosal space. Emphysematous gastritis refers to mucosal disruption caused by gas-forming bacteria invasion. Causes in infants include necrotizing enterocolitis, caustic ingestion, recent abdominal surgery, or gastroenteritis. Pneumatosis intestinalis and specifically gastric pneumatosis are uncommon but potentially dangerous conditions in the burn-injured patient. Risk factors for burn patient include low-flow state, distension and recent trauma or instrumentation. In adults, infection with gas forming organism (Escherichia coli, Proteus, Clostridium welchii and Staphylococcal aureus), gastric outlet obstruction, and instrumentation are the most common cause of gastric pneumatosis. Radiographically the gastric pneumatosis appears linear, cystic, or as small, clustered bubbles in simple KUB films. CT Scan is more sensitive and can further identify the area of pneumatosis in context of portal venous gas. Management of gastric pneumatosis should consist immediate decompression of the stomach with a nasogastric tube. This is followed by a period of stabilization with broad-spectrum antibiotics to reduce bacterial translocation and managing the cause of the pneumatosis. In cases of pyloric stenosis, a pyloromyotomy is performed after preoperative stabilization and correction of electrolytes imbalances. In cases of duodenal obstruction causing gastric pneumatosis management consist of correction of electrolytes disturbances and fluid imbalances, gastric decompression, and subsequent surgical correction of the duodenal obstruction. Clinicians must use the clinical picture in combinations with radiographic evidence to distinguished between gastric emphysema and emphysematous gastritis because there are significant prognostic differences among these pathologies. The mortality for gastric pneumatosis is 41% in adults and 6% in children. 

References:
1- Lim RK, McKillop S, Karanicolas PJ, Scott L: Massive gastric pneumatosis from pyloric stenosis. CMAJ. 182(5):E227, 2010
2- Markel TA, Wanner MR, Billmire DF: Gastric pneumatosis secondary to pyloric stenosis. J Pediatr Surg. 48(3):655-7, 2013
3- Fernandes AR, Smith WG: Case 4: Gastric pneumatosis in an eight-month-old girl. Paediatr Child Health 19(9): 463-64, 2014
4- Bhargava P, Parisi M: Gastric pneumatosis and portal venous gas: benign findings in hyperthrophy pyloric stenosis. Pediatr Radiol 39: 413, 2009
5- Schattner A, Glick Y: Gastric pneumatosis and its varied pathogenesis. QJM. 113(10):747-748, 2020
6- Bisgaard E, Hewgley WP, Gee KM, et al: Gastric Pneumatosis in a Critically Ill Pediatric Burn Patient: Case Report and Overview of Risk Factors, Diagnosis, and Management. J Burn Care Res. 2021 42(2):342-344, 2021

PSU Volume 60 No 06 JUNE 2023

Congenital Neuroblastoma

Neuroblastoma (NB) is the most frequent occurring malignant tumor in the newborn and early infancy. Almost one-fourth of congenital malignant tumors are neuroblastoma. NB is an embryonal malignancy composed of immature cells of the nervous system (sympathogonia) derived from primordial neural crest cells which gives rise to the sympathetic ganglia and the adrenal medulla. More than 90% of NB develop in children aged under five years, with the peak of the disease during the first year of life. In general, infants younger that one year have favorable outcomes, with spontaneous regression of the tumor, whereas children older than 18 months require extensive chemotherapy and treatment. Congenital NB is defined as a NB found within the first month of age. Approximately 20% of cases are diagnosed antenatally, while 16% are diagnosed in the first month of life. Approximately 75% of NB tumors are localized to the adrenal gland, with more than half in the right adrenal gland. Fetal ultrasound has increased the antenatal detection of neuroblastoma. NB can be identified as early as 23 weeks of gestation by US. Though most are seen as solid masses, an unique variant that occurs in the perinatal period is called cystic NB (40% of congenital NB), which is characterized by one or more macroscopic or microscopic cysts within the tumor. This unique variant is benign and can regress spontaneously like other NB that develop in infancy. In addition, this variant has a decreased incidence of metastasis and lower tumor marker levels. Congenital NB usually have normal MYCN copies and even abnormal copy numbers do not have a substantial effect on prognosis in the setting of a localized tumor. A noninvasive diagnostic workup with ultrasound, urine catecholamine level and MIBG scintigraphy can lead to an accurate diagnosis of perinatal NB. NB are heterogenous solid lesions, mostly echogenic, calcification is common, either coarse as focal echogenic areas with usually no distal acoustic shadowing, or fine resulting in diffusely increased echogenicity of the tumor. On CT, NB present as large, heterogenous, lobulated soft-tissue masses that show heterogenous or little enhancement. Coarse, finely stippled, or curvilinear calcifications are seen in 85% of abdominal and 50% of thoracic NB on CT. Low attenuation areas seen within the tumor represent pseudo-necrosis or hemorrhage. Encasement a/o or compression of major abdominal vessels can also be seen. The most common clinical presentation of a neonate born with a NB is a palpable abdominal mass The abdominal mass may occur due to metastasis to liver (hepatomegaly). Masses in the neck, chest and head can also occur. Skin lesions described as blueberry muffin spots are suggestive of disseminated disease. Almost 60% of infants with NB have metastatic disease at presentation. Metastases occur via bloodstream and lymphatics with common sites including liver, skeleton, bone marrow and skin. Compression of the renal artery by the tumor can activate the renin-angiotensin-aldosterone axis and lead to hypertension in the baby. Hypertension and tachycardia can also result from cathecolamines release from the NB. Maternal hypertension and other symptoms have been reported in some cases of fetal congenital neuroblastoma secondary to catecholamines secretion by the tumor. NB is the most common malignancy to involve the placenta. Microscopically the congenital malignant tumors cells are usually confined to the villous capillaries of the fetal circulation occupying the intervillous space of the maternal vascular system. Microscopically, NB is composed mainly of small, rounded blue cells with small rounded or oval nuclei surrounded by a rim of cytoplasm. The presence of delicate nerve fibers is pathognomonic diagnostic sign. NB Stage 4S (the `S' stands for special) is defined as metastatic NB presenting in infants aged less than 12 months, with metastasis limited to skin, liver, and bone marrow (<10% of bone marrow involvement). It is also classified as Stage MS if it occurs in the perinatal period. Patients with localized disease, Stage 4S or Stage MS disease without life-threatening symptoms or adverse genetic features (MYCN amplification or segmental chromosomal abnormalities) carry low risk with most going through spontaneous regression, hence they usually require no treatment. Approximately 90% of perinatal NB have a good prognosis, because the majority of tumors are stage 1 or 2 by the International NB Staging system. Spontaneous regression usually occurs if there are no MYCN amplifications, no loss of chromosome 1p, and near triploid number of chromosomes. Adverse outcomes are highly associated with more than 10 MYCN oncogene copies. Perinatal NB with stage 1, solid with less than 3 cm size, or cystic tumor less than 5 cm can be observed without biopsy. Stage MS or 4S with massive liver enlargement and resultant respiratory and cardiovascular symptoms may require intervention with low dose chemotherapy or radiotherapy. 10% of infants will have stage 4 or stage 4S disease with MYCN amplification and an associated poor prognosis. With only surgery, a younger infant (< 6 months) with localized disease and favorable biology has even better outcome.

References:
1- Kume A, Morikawa T, Ogawa M, et al: Congenital neuroblastoma with placental involvement. Int J Clin Exp Pathol. 7(11):8198-204, 2014
2- Hwang SM, Yoo SY, Kim JH, Jeon TY: Congenital Adrenal Neuroblastoma With and Without Cystic Change: Differentiating Features With an Emphasis on the of Value of Ultrasound. AJR Am J Roentgenol. 207(5):1105-1111, 2016
3- Minakova E, Lang J: Congenital Neuroblastoma. Neoreviews. 21(11):e716-e727, 2020
4- Croteau N, Nuchtern J, LaQuaglia MP: Management of Neuroblastoma in Pediatric Patients. Surg Oncol Clin N Am. 30(2):291-304, 2021
5- Zhang S, Zhang W, Jin M, et al: Biological features and clinical outcome in infant neuroblastoma: a multicenter experience in Beijing. Eur J Pediatr. 180(7):2055-2063, 2021
6- AlZhrani WA, Elimam NA, Almehdar AS, et al: Metastatic 4S neuroblastoma with excellent outcome in Saudi cancer center. Saudi Med J. 42(12):1353-1356, 2021

Ureterocele

Ureterocele are cystic dilatations of the intravesical submucosal ureter. With an incidence of one in 4000 live births, they occur more often in Caucasians and 4-6 times more frequent in females. Ureteroceles are classified as simple (intravesical, orthotopic) or ectopic (extravesical) according to the location of the ureteral orifice, with simple being in the bladder trigone, and ectopic ureterocele in the bladder neck or posterior urethra. Also, ureteroceles are classified as single system ureterocele when there is a normal kidney with only one ureter, or duplex system ureterocele when associated with complete ureteral and renal duplication. The kidney that drains to the ureterocele is frequently hydronephrotic and dysplastic since some degree of obstruction can occur. The bladder can also be obstructed when the ureterocele protrudes into the urethra. Vesicoureteral reflux is frequently associated with an ureterocele. Associated anatomic and pathophysiologic features of ureteroceles in duplex systems include intravesical ureteral obstruction, dysplasia, or obstructive nephropathy of the ureterocele-associated moiety (40-70%), and vesicoureteral reflux (VUR) to the ipsilateral inferior moiety (50%) or contralateral kidney (25%). Presentation of ureterocele can be symptomatic with an infectious process, or asymptomatic with hydronephrosis findings. Recurrent urinary tract infection is the most common presentation at birth. If left untreated, children can develop stone, pyonephrosis, urosepsis, spontaneous rupture of the ureterocele, and even chronic renal failure. Most cases are diagnosed prenatally. The diagnosis of an ureterocele can be performed prenatally in 75% of cases. On prenatal ultrasound the ureterocele presents as a cyst inside the bladder and can be suspected if the fetus shows the presence of two separated noncommunicating renal pelvis and a dilated ureter. The thin wall anechogenic image inside the bladder is known as the "Foley sign". Sometimes the ureterocele can occlude or even protrude through the urethra and a clinical picture of megacystis, bilateral hydronephrosis and oligohydramnios can occur. Prenatal diagnosis of ureterocele improves postnatal outcome, specifically less urinary tract infection and less need for reoperation. Prenatal therapy including ultrasound guided percutaneous drainage, laser treatment or fetoscopy with in utero incision of the ureterocele can be offered in cases of impending renal damage. All prenatally ureteroceles should be referred to pediatric urologist to program postnatal therapy, institute adequate prophylaxis and prevent renal damage. Most ureterocele are associated with complete ureteral and renal duplication systems. The goals of management of ureteroceles include decompression of obstruction, avoiding vesicoureteral reflux, preventing urinary tract infections, promotion of continence, preservation of renal function, and minimizing the number and invasiveness of surgical procedures. Ideal candidate for a conservative management approach to ureterocele include asymptomatic, good, or absent function in ureterocele moiety, absence of grade 3 or 4 VUR, absence of inferior moiety obstruction by scintigraphy, and absence of bladder outlet obstruction. Management of ureterocele might include observation, endoscopic, upper pole nephrectomy, lower tract reconstruction and total nephroureterectomy. Transurethral endoscopic decompression (deroofing, wide excision, single puncture, double puncture) treatment is a widely used treatment. Endoscopic puncture is simple, minimally invasive and can be performed outpatient. Children with a single intravesical ureterocele benefit the most from endoscopic incision. Some have shown that a generous vertical incision along the entire extent of the ureterocele with a period of double J stenting is successful in draining obstructed cases. The use of double J stent appears to reduce the rates of re-stenosis, Successful decompression without reflux can be achieved in 70-80% of such cases. This is not the case of ectopic ureteroceles. Most believe that endoscopic puncture of an ectopic ureterocele is indicated mainly for uncontrollable sepsis and azotemia with bladder outlet obstruction with or without ureterocele prolapse. Reoperation rate after endoscopic decompression is higher in children with ectopic double-system, ectopic vs intravesical and those associated with preoperative VUR than orthotopic single system ureterocele. The main reason for reoperation is ipsilateral reflux. Almost 50% of double system ectopic ureterocele resolve with endoscopic incision, with 40% needing ureteral reimplantation due to symptomatic VUR. VUR after transurethral incision can be safely followed nonoperatively as long as it is asymptomatic, and it may even resolve spontaneously. Bedside puncture of an introital prolapsing ectopic ureterocele obstructing the urethra and bladder neck in females has been reported without anesthesia or sedation. In the case of ectopic ureterocele with a subsphincteric outlet, urinary incontinence can only be restored by a ureteral reimplantation or heminephrectomy. Other alternative in management includes ureteroureterostomy when the upper moiety has significant functionality, pyelopyelostomy, ureteropyelostomy and superior moiety heminephrectomy. Treatment should be individualized depending on renal function, obstruction, drainage of the contralateral ureter, bladder outlet obstruction and associated VUR and UTI.

References:
1- Godinho AB, Nunes C, Janeiro M, Carvalho R, Melo MA, da Graca LM: Ureterocele: antenatal diagnosis and management. Fetal Diagn Ther. 34(3):188-91, 2013
2- Sander JC, Bilgutay AN, Stanasel I, et al: Outcomes of endoscopic incision for the treatment of ureterocele in children at a single institution. J Urol. 193(2):662-6, 2015
3- Timberlake MD, Corbett ST: Minimally invasive techniques for management of the ureterocele and ectopic ureter: upper tract versus lower tract approach. Urol Clin North Am. 42(1):61-76, 2015
4- Chowdhary SK, Kandpal DK, Sibal A, Srivastava RN, Vasudev AS: Ureterocele in newborns, infants and children: Ten year prospective study with primary endoscopic deroofing and double J (DJ) stenting. J Pediatr Surg. 52(4):569-573, 2017
5- Jawdat J, Rotem S, Kocherov S, Farkas A, Chertin B: Does endoscopic puncture of ureterocele provide not only an initial solution, but also a definitive treatment in all children? Over the 26?years of experience. Pediatr Surg Int. 34(5):561-565, 2018
6- Nguyen DH, Brown CT: Puncture of prolapsed ureterocele at bedside without anesthesia or sedation.  J Pediatr Urol. 16(3):390-391, 2020
7- Pani E, Negri E, Cini C, et al: Endoscopic treatment of ureterocele in children: Results of a single referral tertiary center over a 10 year-period. J Pediatr Urol. 18(2):182.e1-182.e6, 2022

Polycystic Kidney Disease

Polycystic kidney disease (PKD) has two genetic variants: autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). ADPKD is the most common inherited human renal disease (1:1000), 85% of cases are caused by mutations in the PKD1 on chromosome 16, and 15% are caused by mutations in the PKD2 on chromosome 4. Males and females are equally affected. In general, renal disease is more severe in males, but more than 80% of patients with ADPKD and severe polycystic liver disease are females. ADPKD accounts for 5% of ESRD development in adults. ADPKD is generally a late onset (5th through 7th decade of life) systemic disease characterized by bilateral progressive enlargement of focal fluid filled cysts occurring in the distal region of the nephron and collecting ducts with variable extrarenal manifestation. Extrarenal manifestation of ADPKD include cystic lesions in the liver, pancreas, spleen and seminal vesicles, vascular anomalies such as intracranial aneurysms, aortic root dilatation, thoracic aorta dissection, mitral valve prolapse, abdominal and inguinal hernias, along with early onset hypertension. The kidney cysts in ADPKD form in utero. Majority of ADPKD are diagnosed in adulthood, though the disease can present in children of all ages from fetus to adolescents. Clinical manifestations include left ventricular hypertrophy, hypertension, proteinuria, hematuria, nephrolithiasis, flank pain and impaired renal function. The clinical spectrum of ADPKD can go from a severe neonatal condition to asymptomatic development of renal cysts. ADPKD can also be a component of the inherited disease tuberous sclerosis. ARPKD is much rarer (1:10000), primarily affecting two organs, kidney, and liver, belongs to a group of congenital hepatorenal fibrocystic syndromes and is a cause of significant renal and liver-related morbidity and mortality in children during the1st and 2nd decade of life. ARPKD is commonly diagnose in utero or at birth and occurs as a result of mutations in a single gene called the polycystic kidney and hepatic disease 1 (PKHD1). Affected fetus develop oligohydramnios, pulmonary hypoplasia (Potter's syndrome), and massively enlarged echogenic kidneys with death occurring in 20-40% of affected babies due to respiratory insufficiency (pulmonary hypoplasia). Almost 50% of children develops end-stage renal disease during the first decade of life. Disease liver due to cysts also occurs with an estimate of 40% having severe dual organ disease. Overall renal survival rate is only 42% by adulthood. Morbidity is caused by hypertension, progressive renal failure, progressive periportal congenital hepatic fibrosis, esophageal/gastric varices, enlarged hemorrhoids, splenomegaly, hypersplenism and GI bleeding. Intrahepatic bile duct dilatation (Caroli's syndrome) occurs in 30% of ARPKD children. Management of portal hypertension might entail endoscopic band ligation and porto-systemic shunting, sometimes needing dual liver/kidney transplant. All inherited cystic kidney disease are due to mutations in the cilia or basal body/centrosome complex. Both genetic variants of PKD are known as ciliopathies due to abnormal cilia structure and function. The primary cilia is thought to function as mechanosensor that translate mechanical signals such as fluid flow into chemical signals within epithelial and endothelial cells. Both ADPKD and ARPKD are characterized by cystic dilatations of the renal collecting tubules.  ARPKD cyst are smaller in size, all the collecting tubules are involved and manifests as fusiform dilatation radiating from cortex to medulla. Cysts compress tissue and reduces renal function, while compression of blood vessels by the cysts leads to hyperreninemic hypertension. Renal cysts present in dysplastic kidneys is called multicystic dysplastic kidneys. Ultrasound is the most common imaging modality used to diagnose ADPKD. Total kidney volume is the standard biomarker for evaluating disease progression with CT or MRI. Genetic diagnostic testing is not necessary for clinical practice. There are currently no disease-specific therapy available from PKD. Current therapy for both ADPKD and ARPKD children and adults that have reach renal failure is limited to dialysis and transplantation. There is promising pharmacological agents to prevent ADPKD progression which are beyond the scope of this review. Treatment is directed at managing or preventing complications of the disease such as hypertension (ACE inhibitors), left ventricular hypertrophy, mitral valve prolapse, urolithiasis, pain management and urinary tract infections. Approximately 50% of patients with ADPKD will progress to end-stage renal disease.

References:
1- Sweeney WE Jr, Avner ED: Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy. Pediatr Res. 75(1-2):148-57, 2014
2- Guay-Woodford LM, Bissler JJ, Braun MC, et al: Consensus expert recommendations for the diagnosis and management of autosomal recessive polycystic kidney disease: report of an international conference.  J Pediatr. 165(3):611-7, 2014
3- Baum M: Overview of polycystic kidney disease in children. Curr Opin Pediatr. 27(2):184-5, 2015
4- Bergmann C, Guay-Woodford LM, Harris PC, Horie S, Peters DJM,  Torres VE: Polycystic kidney disease. Nat Rev Dis Primers. 4(1):50, 2018
5- Benz EG, Hartung EA: Predictors of progression in autosomal dominant and autosomal recessive
polycystic kidney disease. Pediatr Nephrol. 36(9):2639-2658, 2021
6- Nishio S, Tsuchiya K, Nakatani S, et al: A digest from evidence-based Clinical Practice Guideline for Polycystic Kidney Disease 2020. Clin Exp Nephrol. 25(12):1292-1302, 2021
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