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case records of themassachusetts general hospital

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 366;4 nejm.org january 26, 2012 361

Founded by Richard C. CabotNancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate EditorJo-Anne O. Shepard, m.d.,Associate Editor Alice M. Cort, m.d.,Associate EditorSally H. Ebeling,Assistant Editor Christine C. Peters, Assistant Editor

Case 3-2012: A Newborn Boy with Vomiting,Diarrhea, and Abdominal Distention

Elliot Melendez, M.D., Allan M. Goldstein, M.D.,Pallavi Sagar, M.D., and Kamran Badizadegan, M.D.

From the Department of Pediatrics, Chil-drens Hospital (E.M.); the Departmentsof Pediatrics (E.M.), Surgery (A.M.G.), Radi-ology (P.S.), and Pathology (K.B.), Massa-chusetts General Hospital; and the Depart-ments of Pediatrics (E.M.), Surgery (A.M.G.),Radiology (P.S.), and Pathology (K.B.), Har-vard Medical School all in Boston.

N Engl J Med 2012;366:361-72.Copyright 2012 Massachusetts Medical Society.

Presentation of Case

Dr. Rebecca C. Bell (Pediatrics): A 6-day-old boy was admitted to this hospital becauseof vomiting, diarrhea, and abdominal distention.

The patient was born at another hospital to a teenaged primigravida by vaginaldelivery after a full-term, uncomplicated gestation. The mother had received pre-natal care; she had no history of sexually transmitted infections, and prenatalscreening tests were negative. Meconium was present at delivery. The patientsbirth weight was 4.3 kg (95th percentile), and the 1-minute and 5-minute Apgarscores were 7 and 9, respectively. Breast-feeding was initiated. The newborn passedtwo stools on the second day (the first at 30 hours of age). The next day, he report-edly had one loose, green stool. He was discharged home at 50 hours of age. Helived with his mother and her parents. When he was 3 and 4 days of age, he vom-ited yellow-green emesis on several occasions. He was otherwise well and breast-feeding regularly. At 3 a.m. on the day of admission, he became fussy and did notcomplete his normal feeding. Between 3 a.m. and 9 a.m., approximately six epi-sodes of vomiting (initially breast milk, followed by mucus) occurred, with in-creasingly foul-smelling emesis. Diarrhea developed, and urine output decreased.Later that morning, he became less active; abdominal distention developed, andhe stopped voiding. He was taken to a clinic affiliated with this hospital. On ex-amination, he appeared tired, with intermittent grunting. The rectal temperaturewas 38.0C. The abdomen was distended and tender, with hypoactive bowel sounds;stool was positive for occult blood. He was transported by ambulance to the emer-

gency department of this hospital.On examination, the patient appeared alert and slightly uncomfortable. The tem-perature was 37.2C, the pulse 160 beats per minute, the respiratory rate 30 breathsper minute, and the oxygen saturation 100% while he was breathing ambient air.The weight was 3.9 kg. The abdomen was distended, soft, and tympanic, with de-creased bowel sounds. There were small, bilateral noncommunicating hydroceles.The remainder of the examination was normal. A stool specimen showed no occultblood. Urinalysis revealed clear orange urine, with a specific gravity greater than1.030, pH 6.5, nitrites, 1+ urobilinogen, 3+ bilirubin, 2+ albumin, and trace whitecells, blood, glucose, and ketones. Urinalysis also revealed 0 to 2 red cells, 3 to 5 white

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n engl j med 366;4 nejm.org january 26, 2012362

Table 1. Laboratory Data.*

VariableReference Range,

Age-Adjusted On Admission 2nd Hospital Day 3rd Hospital Day

Hematocrit (%) 45.067.0 66.0 (manual) 62.6 48.8

Hemoglobin (g/dl) 14.522.5 21.0 16.3

White-cell count (per mm3) 940034,000 14,300 7000 6200

Differential count (%)

Neutrophils 5362 29 24 18 (ref 3048)

Band forms 010 19 1

Lymphocytes 2134 32 53 61 (ref 4081)

Monocytes 411 15 17 18

Eosinophils 08 4 0

Basophils 03 1 2

Metamyelocytes 0 5 1

Platelet count (per mm3) 150,000450,000 179,000 157,000 65,000

Sodium (mmol/liter) 135145 138 136 140

Potassium (mmol/liter) 4.05.6 7.1 (hemolyzed) 3.5 3.5

Chloride (mmol/liter) 98106 113 110 110

Carbon dioxide (mmol/liter) 19.022.0 17.1 22.5

Urea nitrogen (mg/dl) 520 46 34 19

Creatinine (mg/dl) 0.301.00 0.60 0.43

Glucose (mg/dl) 60100 141 185 124Bilirubin (mg/dl)

Total 2.015.0 0.7 0.8

Direct 0.53.5 0.1 0.1

Protein (g/dl)

Total 6.08.3 3.2 3.3

Albumin 3.35.0 1.6 1.9

Globulin 2.64.1 1.6 1.4

cells, moderate bacteria, and a few squamous andrenal tubular cells per high-power field. Ampicil-lin, gentamicin, and boluses of normal saline wereadministered. Other test results are shown inTable 1. Radiographs of the abdomen showeddilated loops of bowel in the lower abdomen,which were suggestive of distal bowel obstruc-

tion. There was no free air. An upper gastro-intestinal series showed severe gastroesophagealreflux without evidence of malrotation. An en-ema administered with a water-soluble contrastagent revealed free flow of contrast material,with a long segment of narrowing involving therectum and distal sigmoid colon and proximaldistention of the descending colon. No stricturewas identif ied. Rectal examination performed

after the enema did not reveal blood or mucus.After the enema, the patient passed multiple non-bloody stools, and the abdominal distentiondecreased.

Seven hours after arrival in the emergency de-partment, the temperature rose to 38.7C; acet-aminophen was administered. Lumbar puncture

was performed; analysis of cerebrospinal fluid isshown in Table 2. Acyclovir was administered.The patient was admitted to the pediatric service.Shortly after admission, the temperature rose to39.1C and the pulse to 179 beats per minute, withpoor capillary refill. He was transferred to thepediatric intensive care unit. Vancomycin andadditional crystalloid were administered intrave-nously. During the first day, increasing abdomi-




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case records of the massachusetts general hospital


nal distention, poor perfusion (as evidenced bycool extremities), and respiratory failure devel-oped. A nasogastric tube was placed.

A continuous infusion of dopamine followedby norepinephrine was administered, and the tra-chea was intubated. Transthoracic echocardiogra-phy revealed a patent foramen ovale, a smallpatent ductus arteriosus with left-to-right shunt-

ing, and normal ventricular function. Stoolsbecame positive for occult blood, and perianalexcoriation developed. Serum levels of lactate,aspartate aminotransferase, and alkaline phos-phatase were normal; other test results are shownin Table 1. A repeat abdominal radiographshowed multiple distended loops of small bowelcontaining residual contrast material and relativedecompression of the large bowel. Surgical con-sultants inserted a femoral central venous cathe-

ter and a radial arterial catheter. The administra-tion of ampicillin was stopped, and meropenemwas begun; pressors were adjusted to maintain amean arterial pressure between 50 and 60 mm Hg.

Urine obtained by catheter on admission wascultured and grew few nonhemolytic streptococci(1000 to 10,000 colonies per milliliter; the strep-tococci were consistent with viridans group

streptococci and were thought to be a contami-nant); a blood culture was sterile. Screening ofnasal specimens for respiratory viruses and en-terovirus and of stool cultures for enteric patho-gens and enterovirus was negative. On the thirdday, serum levels of lactate, magnesium, andionic calcium were normal; other test results areshown in Table 1. Bicarbonate and immune globu-lin were administered intravenously. Total paren-teral nutrition was begun.

Table 1. (Continued.)

VariableReference Range,

Age-Adjusted On Admission 2nd Hospital Day 3rd Hospital Day

Phosphorus (mg/dl) 4.59.0 3.0

Calcium (mg/dl) 8.510.5 7.3

Alanine aminotransferase (U/liter) 1055 88 65

d-Dimer (ng/ml)

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Table 2. Analysis of Cerebrospinal and Peritoneal Fluid.*

Variable Cerebrospinal Fluid Peritoneal Fluid

Reference Range Day of Admission Reference Range 6th Day

Color and turbidity Colorless, clear Colorless, clear Yellow, clear Yellow, slightly turbid

White-cell count (per mm3) 01000 1130 (11% neutrophils, 1% bandforms, 81% lymphocytes, 1%

monocytes, 6% plasma cells)

Tube 1 030 37 (29% lymphocytes, 71% mono-cytes)

Tube 4 030 11 (2% neutrophils, 21% lympho-cytes, 73% monocytes, 4%macrophage or lining cells)

Red-cell count (per mm3) 0 1585

Tube 1 0 21

Tube 4 0 0

Glucose (mg/dl) 5075 120

Protein (mg/dl) 555 48 Not defined 2200

Sodium (mmol/liter) Not defined 139Potassium (mmol/liter) Not defined 3.2

Chloride (mmol/liter) Not defined 105

Carbon dioxide (mmol/liter) Not defined 32.2

Lactate dehydrogenase (U/liter) Not defined 140

Amylase (U/liter) Not defined

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and results of renal- and hepatic-function testsimproved. Acyclovir and vancomycin were stopped,and furosemide was administered for gradualdiuresis.

During the second week, the patients vitalsigns and clinical condition gradually stabi-lized. Gentamicin and dopamine were stopped,

norepinephrine was weaned, and gradual diure-sis continued.

On the 14th day, a diagnostic procedure wasperformed.

Differential Diagnosis

Evaluation and Management of Neonatal Sepsis

Dr. Elliot Melendez: All discussants are aware of thediagnosis in this case. This 6-day-old boy presentedwith signs of sepsis. Although viruses are themost common infectious cause of fever in infants,

the prevalence of urinary-tract infection, bacte-remia, and meningitis in patients less than 28 daysold is between 8.8% and 13.3%.1,2 For this reason,cultures from urine, blood, and cerebrospinal fluidwere obtained. The most common bacterial patho-gens are group B streptococci, Escherichia coli, andListeria monocytogenes: thus, the administration ofbroad-spectrum antibiotics was initiated. Herpessimplex virus, a dangerous but potentially treat-able virus, was considered, and the administrationof acyclovir was initiated. Stool was reported asheme-positive in the clinic; it was heme-negativewhen the patient arrived at this hospital, but be-cause of the abdominal distention, an abdominalsource was considered. If bloody diarrhea is pres-ent, stool cultures for enteric bacterial pathogensmust be sent. Appropriately, the neonate was ad-mitted for observation and continuation of anti-biotics pending culture results. On admission, hewas recognized as having respiratory distress andcardiovascular dysfunction, as evidenced by poorcapillary refill. He was transferred to the pediat-ric intensive care unit, where respiratory failure

subsequently developed, and his condition metthe consensus definition of severe sepsis.3

Severe sepsis with shock is associated withan imbalance between oxygen delivery and de-mand. The treatment strategy to correct this im-balance is referred to as early goal-directed thera-py. Rivers et al.4 found that in adults a sepsisalgorithm with targeted goals in managementcan reduce mortality rates among patients withsevere sepsis and shock. Unfortunately, in pedi-

atrics, there are very little data on the use of earlygoal-directed therapy beyond aggressive fluid ad-ministration. Nevertheless, the principles of earlygoal-directed therapy are the same for both chil-dren and adults.

Oxygen was administered to improve oxygendelivery. If there are signs of respiratory insuf-

ficiency, early endotracheal intubation should beconsidered, as it was in this neonate. The historysuggested the presence of absolute hypovolemia,probably due to increased insensible water lossesfrom fever and tachypnea, as well as vomiting,diarrhea, and poor oral intake. Aggressive fluidresuscitation was given in the form of 0.9% salinein boluses of 20 ml per kilogram of body weightover a period of 5 to 10 minutes and repeatedas long as signs and symptoms of shock per-sisted. Ringers lactate would also have beenacceptable. After the administration of 60 ml per

kilogram, vasopressor therapy should be admin-istered if the blood pressure remains low; how-ever, more fluid can safely be given as long asthere is no evidence of heart failure or volumeoverload.

Children are more likely than adults to havecardiac dysfunction in severe sepsis or shock,with 58% having low cardiac output and highsystemic vascular resistance and 22% having bothlow cardiac output and low systemic vascular re-sistance.5 As a result, because of its vasopressiveand inotropic properties, the administration ofdopamine was begun in this patient. The use ofsubsequent agents should depend on the clinicalresponse and the predominant hemodynamicderangement. Because this patient had persis-tent shock with vasodilatation (warm shock),norepinephrine was subsequently added. Oncethe neonate was receiving dopamine and norepi-nephrine, an echocardiogram was obtained, whichruled out congenital heart disease.

Adequate control of fever can reduce meta-bolic activity and oxygen demand. Since some

children have tachypnea or agitation, early con-trol of the airway with sedation and analgesia,as was performed in this patient, can also bebeneficial. Finally, prompt empirical treatmentof infection can reduce the metabolic demand bythe inflamed tissue.

Finally, a search should continue for a poten-tial source of infection that can be controlled.Patients with infected indwelling foreign objects,such as central catheters, should have these objects




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removed. Patients with necrotic wounds shouldundergo dbridement. Abscesses should be drained,preferably by minimally invasive techniques. Inthis patient, who had progression of abdominaldistention and development of bloody stools, anintraabdominal source of infection was likely,and we requested surgical consultation to assist

with further evaluation and treatment.

Bilious emesis, liquid stools, and abdominal

distention in a neonate

Dr. Allan M. Goldstein: This neonate presented withbilious emesis, liquid stools, and abdominal dis-tention. In the differential diagnosis of a poten-tial intraabdominal process in this newborn, life-threatening conditions need to be considered first.

Intestinal Malrotation

Bilious emesis in newborns immediately raises

concern for intestinal malrotation with midgutvolvulus, a condition requiring prompt treatment.Abdominal distention and heme-positive diar-rhea, as in this patient, can occur in malrotationwith intestinal ischemia. A timely upper gastro-intestinal series should be performed to rule outmalrotation.

Necrotizing Enterocolitis

Necrotizing enterocolitis typically occurs in pre-mature neonates, although 10% of cases occur infull-term neonates.6 The onset of necrotizing en-terocolitis in premature neonates is often delayed,but in full-term neonates it can develop within thefirst week of life.6 Necrotizing enterocolitis is un-likely in this patient because of the absence of pneu-matosis intestinalis on abdominal radiographs.

Enterocolitis Associated with Hirschsprungs Disease

Enterocolitis associated with Hirschsprungs dis-ease (Hirschsprungs-associated enterocolitis) isa critical diagnosis that fits this newborns pre-sentation. Patients with Hirschsprungs disease,

a congenital intestinal neuropathy characterizedby the absence of ganglion cells extending fromthe rectum proximally for a variable distance, pre-sent with failure to pass meconium within 48 hoursafter birth and often progress to abdominal dis-tention and vomiting.7 In healthy newborns, 94 to99% pass meconium by 24 hours, and 100% by48 hours.8,9 In newborns with Hirschsprungs dis-ease, only 6% pass meconium by 24 hours,7 and37 to 54% by 48 hours7,10 This patient first passed

meconium at 30 hours of life, a finding consis-tent with Hirschsprungs disease. Vomiting, dis-tention, loose stools, and fever occur, as in thispatient, when Hirschsprungs disease is compli-cated by enterocolitis. In children with knownHirschsprungs disease, enterocolitis is the mostserious complication. Even in infants and neonates

without known Hirschsprungs disease, the diag-nosis should be considered, since up to 12% of pa-tients who are ultimately found to have Hirsch-sprungs disease present with enterocolitis.11,12Infectious gastroenteritis, allergic colitis (allergyto milk protein), and metabolic disorders arealso possible in this patient but should be consid-ered only after the critical diagnoses of Hirsch-sprungs disease and enterocolitis have beenruled out.

May we review the imaging studies?Dr. Pallavi Sagar: Radiographs of the abdomen

taken with the patient in the supine and decubi-tus positions (Fig. 1A and 1B, respectively) re-veal dilated loops of bowel with airliquid levelsin the right abdomen, as well as a small-caliberrectum. These findings are worrisome for ob-struction of the distal bowel. There is no free airor pneumatosis. An upper gastrointestinal series(Fig. 1C) shows severe, spontaneous gastroesoph-ageal reflux. There is no evidence of malrotation.An enema administered with a water-soluble con-trast agent (Fig. 1D) reveals free flow of contrastmaterial from the rectum to the ascending colonwithout evidence of a stricture. There is narrow-ing of a long segment that has an irregularmucosal outline and involves the rectum anddistal sigmoid colon, with reversal of the recto-sigmoid index and a funnel-like transition into adilated proximal sigmoid and descending colon.The transverse colon and ascending colon arealso dilated. These findings are worrisome fordistal bowel obstruction secondary to Hirsch-sprungs disease. The irregular mucosal outlinemay represent dyskinetic contractions of the

aganglionic segment or colitis.An abdominal ultrasonogram obtained onthe fifth hospital day (Fig. 1E) shows abundantascites with multiple internal septations, fea-tures of concern for peritonitis. Overall, thesefeatures suggest distal bowel obstruction, mostlikely due to Hirschsprungs disease, with colitisand peritonitis.

Dr. Goldstein: The findings on a barium enemaexamination a contracted rectosigmoid with a




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dilated descending colon are characteristic ofHirschsprungs disease, and the sawtooth patternof irregularity in the rectal mucosa is of concern

for enterocolitis. These clinical and radiographicfeatures all point to the diagnosis of Hirsch-sprungs disease with Hirschsprungs-associatedenterocolitis. Prompt recognition and early treat-ment are essential. A definitive diagnosis ofHirschsprungs disease requires examination ofa rectal-biopsy specimen to confirm agangliono-sis. However, because of the acute inflammationin this patient, performing the biopsy needs tobe deferred until the inflammation subsides,

and treatment must be initiated on the basis ofa presumptive diagnosis.

The incidence of enterocolitis in patients with

Hirschsprungs disease varies widely, from 17% to34%,11-14 partly because of a lack of a standardizeddefinition. Patients with Hirschsprungs-associ-ated enterocolitis can present with symptoms rang-ing from mild abdominal distention with diar-rhea to septic shock, as in this patient.11,15,16

Lethargy and bloody stools can occur. Even milddiarrhea and abdominal distention in a patient withHirschsprungs disease or in a neonate such as thisone, with delayed passage of meconium, should

A B

DC E

Figure 1. Radiographic and Ultrasound Images of the Abdomen.

Supine (Panel A) and left lateral decubitus (Panel B) views show dilated loops of bowel with airliquid levels and

without evidence of rectal air, features suggestive of distal bowel obstruction. There is severe spontaneous gastro-esophageal reflux to the cervical esophagus (Panel C, arrow). An enema administered with a water-soluble contrast

agent (Panel D) reveals narrowing of the rectum and sigmoid (arrow) with funnel transition to the descending colon(arrowhead). Mucosal irregularity of the narrowed segment suggests dyskinetic irregular contractions or colitis. An

abdominal ultrasonogram (Panel E) shows ascites with internal septations (arrow) that are suggestive of peritonitis.




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prompt consideration of Hirschsprungs-associatedenterocolitis in order to avoid a delay in treatmentand the associated complications. Hirschsprungs-associated enterocolitis remains the leadingcause of death in patients with Hirschsprungsdisease, although with increased awareness,earlier diagnosis, and improved management,

the mortality rate associated with the disease hasdecreased from 33%15 to approximately 1%.13

Management of Hirschsprungs-Associated Enterocolitis

Mild cases of Hirschsprungs-associated entero-colitis can be treated with oral metronidazoleand rectal dilatation to relax the anal sphincterand allow the passage of stool. This patient pre-sented with severe enterocolitis, which requireshospitalization, bowel rest, and broad-spectrumantibiotics that target bowel flora.13 Rectal irriga-tion twice daily with 30 to 50 ml of warm saline

applied through a flexible rectal catheter untilthe eff luent is clear, performed to evacuate stoolfrom the colon, is an important component oftreatment.15 Rectal irrigations or dilatations,which could have decreased the severity and du-ration of this patients illness, were not per-formed. In patients whose condition does notimprove with these measures, colostomy or ileos-tomy can be life-saving. This newborns condi-tion ultimately improved with aggressive medicalsupport, and he did not require diversion.

After the enterocolitis resolves in this patient,tissue obtained by rectal suction biopsy shouldbe examined to confirm the diagnosis ofHirschsprungs disease, and then definitive sur-gery should be planned to remove the agangli-onic bowel. Despite definitive surgery, this pa-tient is at risk for recurrence of enterocolitis.Recurrence occurs in 10 to 42% of patients; thereasons are unclear.13,16-19 Trisomy 21 has beenidentified as a risk factor for Hirschsprungs-associated enterocolitis,12,20 as have long-segmentaganglionosis,11,14 prior enterocolitis,11,14 and anas-

tomotic stricture.21,22

Most important, the patientsfamily must be made aware of the early signs ofenterocolitis and the importance of seekingprompt evaluation, and clinicians need to remainvigilant for this devastat ing Hirschsprungs-related complication.

Dr. Elliot Melendezs Diagnosis

Severe sepsis most likely due to an intraabdominalsource.

Dr. Alla n M. Goldsteins

Diagnosis

Hirschsprungs disease complicated by entero-colitis.

Pathological Discussion

Dr. Kamran Badizadegan: The first diagnostic pro-cedure was a suction biopsy that was performedto obtain rectal tissue. Alternative surgical pro-cedures, such as deep mucosal or full-thicknessrectal biopsies, may also be performed but oftenare not because of the increased risk of complica-tions. The diagnosis of Hirschsprungs diseaserequires an adequate volume of the submucosa toconfirm the absence of ganglion cells. In thiscase, the specimen was small, yielding fewerthan 25 consecutive 5-m sections with super-

ficial submucosa (Fig. 2A). Criteria for specimenadequacy vary, although a mucosal-biopsy speci-men measuring 2 to 3 mm in diameter and 1 mmin depth is generally considered adequate for di-agnosis.23 The diagnosis of Hirschsprungs dis-ease is confirmed by the absence of ganglioncells on at least 75 consecutive 5-m sections oftissue.23 Thus, although no ganglion cells wereidentif ied, the small specimen precluded defini-tive evaluation for Hirschsprungs disease. A re-peat biopsy was therefore recommended, and anadequate specimen was obtained (Fig. 2B), withno identifiable ganglion cells in 90 consecutivesections, a f inding consistent with Hirschsprungsdisease.

Ideal specimen size and technical quality arenot always achieved; therefore, the diagnosis ofHirschsprungs disease is often supported bysecondary or ancillary criteria, such as analysisof submucosal nerve fibers, histochemical stain-ing for acetylcholinesterase, and immunostainingfor calretinin. Hypertrophic submucosal nervesmeasuring more than 40 m in diameter are

highly characteristic of Hirschsprungs disease.24

Although it is assumed that this f inding representscompensatory hypertrophy of extrinsic nerves inthe absence of intrinsic neurons, data to supportthis hypothesis are lacking. Support of the diag-nosis in this case was provided by identification ofhypertrophic submucosal nerves (Fig. 2B). His-tochemical staining for acetylcholinesterase onfrozen sections of mucosal-biopsy specimens inHirschsprungs disease often reveals the presenceof abnormal acetylcholinesterase-positive neurites




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within the muscularis mucosae and has long beenan invaluable ancillary technique. In this case, weidentified abnormal acetylcholinesterase-positiveneurites on a frozen-section slide (Fig. 2C).

Studies published after this patients diagnosiswas established indicate that the absence ofcalretinin-positive mucosal neurites on immuno-histochemical staining of paraffin sections is ahighly sensitive marker for Hirschsprungs dis-ease.25,26 Calretinin is a calcium-binding proteinthat is normally expressed in cholinergic nerves;it is not known why calretinin-positive mucosalneurites are absent in Hirschsprungs diseaseand abnormal acetylcholinesterase-positive neu-rites are present. Retrospectively, the original

suction-biopsy specimen was immunostainedfor calretinin and shows complete absence ofcalretinin-positive neurites (Fig. 2D and 2E). Theavailability of this stain may permit the diag-

nosis of Hirschsprungs disease on specimensthat were previously considered inadequate.25,26

There was no evidence of active colitis on eitherbiopsy.

Discussion of M anagement

Dr. Goldstein: The biopsy in this case confirmedthe diagnosis of Hirschsprungs disease. Defini-tive management requires resection of the agan-glionic segment of colon, bringing normally in-

A B

DC E

Figure 2. Suction-Biopsy Specimens of Rectal Tissue.

The original rectal tissue obtained with the use of a suction-biopsy instrument (Panel A, hematoxylin and eosin) did

not show ganglion cells, but the biopsy specimen was considered too small for definitive diagnosis of Hirschsprungsdisease. However, a specimen from the repeat suction biopsy (Panel B, hematoxylin and eosin) contained ample sub-

mucosa with no ganglion cells on more than 90 serial sections and markedly hypertrophic nerves (arrowheads). In

addition, histochemical staining for acetylcholinesterase on an accompanying frozen-section slide (Panel C) highlightedthickened and irregular neurites within the lamina propria and the muscularis mucosae (arrowheads), supporting thediagnosis of Hirschsprungs disease. The original biopsy specimen (Panel A) was retrospectively immunostained for

calretinin (Panel D) and showed a complete absence of calretinin-positive elements, a feature consistent with thisdiagnosis (immunoperoxidase stain for calretinin). Normal expression of calretinin-positive neurites is highlighted

in a control specimen (Panel E, arrows; immunoperoxidase stain for calretinin). The solid bar represents 200 m inPanels A and B, and 50 m in Panels C, D, and E.




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disease, whose intestinal tracts seem particularlysensitive to any perturbations. It is often difficultto determine whether the symptoms are due togastroenteritis or enterocolitis. However, it is bet-ter to assume that it is enterocolitis and treat withantibiotics and rectal irrigations or dilatations,since enterocolitis can progress rapidly, as was

seen in this newborn. This case emphasizes that,even after the aganglionic colon has been re-moved, one must remain vigilant for the diagno-sis of enterocolitis, since the risk persists.

Dr. Nancy Lee Harris(Pathology): Dr. Cronin, youare this patients pediatrician. Would you tell ushow he is doing?

Dr. Rebecca M. Cronin (Pediatrics): This patientis now 2 years old and is doing well medically,despite all his hospital admissions. The pri-mary care of a patient such as this one with achronic medical illness requires educating the

family about the potential complications of thisillness and the potential for recurrence. Althoughthe patients mother is very young, she has doneremarkably well caring for him and has broughthim promptly to medical attention when neces-sary. One issue this family has had to deal withis behavioral problems. Chronically ill and fre-quently hospitalized children are often seen asvulnerable, and it is hard for parents to consis-tently and appropriately discipline them. Forexample, toilet training for this patient is goingto require consistent limit setting. Since lifelongconstipation is a serious possible consequenceof Hirschsprungs disease, establishing goodbowel habits will be important to his overallhealth. We have involved child life specialists

and early intervention specialists, who can helpwith developing good skills for parenting illchildren.

Dr. Harris: Are these parents at risk for havinganother affected child?

Dr. Goldstein: Hirschsprungs disease is a multi-factorial disorder with complex inheritance.

The risk to a subsequent sibling is higher if theaffected child is female or has long-segmentdisease. In this case, which involved a boy withshort-segment aganglionosis, the risk of Hirsch-sprungs disease in a sibling is only 3 to 5%.Because of the low penetrance associated witha single gene mutation in nonsyndromic Hirsch-sprungs disease, the utility of genetic testingcurrently is limited.

Dr. Harris: Is there an algorithm in the neonatalunits that would lead one to raise the questionof Hirschsprungs disease early in the course?

Dr. Goldstein: The possibility of Hirschsprungsdisease should at least be considered in a full-term neonate who does not pass a first meco-nium stool within 24 hours after birth.

Anatomical Di agnosis

Hirschsprungs disease with enterocolitis.

This case was discussed at Pediatric Grand Rounds.Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.Dr. Badizadegan is currently at Nemours Childrens Hospital,

Orlando, FL.We thank Ian Michelow, M.D. (Pediatric Infect ious Diseases),

Phoebe Yager, M.D. (Pediatr ic Intensive Care), and Daniel Ryan,M.D. (Pediatric Surgery), for assistance with preparing the casehistory; and Lindsay P. Carter, M.D. (Pediatrics), for helping toorganize the conference.

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Pediatr Adolesc Med 1999;153:508-11.3. Goldstein B, Giroir B, Randolph A.International pediatric sepsis consensusconference: definitions for sepsis and or-gan dysfunction in pediatrics. Pediatr CritCare Med 2005;6:2-8.4. Rivers E, Nguyen B, Havstad S, et al.Early goal-directed therapy in the treat-ment of severe sepsis and septic shock.N Engl J Med 2001;345:1368-77.5. Ceneviva G, Paschall JA, Maffei F,

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