Patient Presentation
A 6-year-old male came to the dentist because of a swollen lip and a white lesion. He had a filling and metal crown placed the morning before and 8 hours later began to develop swelling of his lower right lip that progressed over 1.5 hours. Initially it was just swollen but then began developing the white lesion. He did not have any pain, difficulty breathing, or obvious trauma to the area. He had been well throughout the day after the dental procedure, and had eaten his normal food and denied biting his lip. His mother called the dentist that evening who was not sure what the problem was but was comfortable watching it over the night as he seemed otherwise well. In the morning he went to the dentist for re-evaluation. He was not taking any medications and had received the same local anesthetic he had previously received without problems.

The past medical history was negative.

The family history was negative for any allergies to foods, drugs, and metals.

The review of systems was negative for any difficulties breathing, other areas of swelling, fever, rhinitis, sore throat, rashes, or halitosis.

The pertinent physical exam showed a well-appearing male in no distress. His vital signs were normal as were his growth parameters. His right lower lip was swollen from just inside the corner of the mouth to approximately 1/3 of the lip. On the buccal mucosa was a 0.5 cm flat uniformly white lesion that was non-painful and was not actually ulcerated. There was slight erythema around the edge of the lesion but no evidence of trauma. There was a small spot at the angle of mandible where the local anesthetic had been previously given. All the soft tissues including around the new crown were normal.

The dentist consulted an oral pathologist who felt that the history and physical examination were consistent with the diagnosis of idiopathic localized angioedema. The pathologist said that this was more common in adults but did occasionally occur in children. The mother was instructed to give him diphenhydramine and monitor him for signs of respiratory distress or rashes and was told that this would slowly improve.

The patient’s clinical course showed that he slowly improved and had complete resolution by 6 days.

Figure 73 - Clinical image showing the flat, white, non-ulcerated lesion on the buccal mucosa.

Discussion
Angioedema is edema that is non-pitting and self-limited. It occurs in non-dependent areas usually in an asymmetric distribution usually on the lips, face, hands, feet, genitals and also in the bowel (causing acute abdominal pain). It usually develops over minutes to hours (often 1-2 hours) with resolution usually within 24-48 hours. Angioedema often occurs with urticaria but 20% of patients may have angioedema as an isolated finding. Pain, warmth and erythema also may occur with the affected area. Intraoral lesions are often white (i.e. leucoplakic).

Angioedema is similar to urticaria but affects the deeper dermis and subcutaneous tissues. Triggers cause the degranulation of mast cells or kinin formation. Acute allergic angioedema is often caused by drugs (including antibiotics and non-steroidal anti-inflammatory drugs), foods, infections, insects, various organic substances (i.e. latex, preservatives, formaldehyde, etc.), and other allergens such as animal danders, dust mites, pollens and molds. Common triggers in children are infections including the viruses Coxsackie A, Epstein-Barr virus, Hepatitis B, and Herpes simplex. Bacterial causes include otitis media, pharyngitis, sinusitis and urinary tract infections. Parasitic infections causing angioedema include filariasis, strongyloides and toxocara. Physical factors can cause mast cell release causing angioedema. These include exposure to cold, heat, pressure, the sun and vibration. In the patient above, the dental work would have exposed the child to pressure and vibration and possibly to changes in heat and/or cold.

The differential diagnosis for angioedema includes:

• Cellulitis of the face
• Cheilitis granulomatosa (i.e. recurrent angioedema episodes with permanent enlargement of the lip)
• Contact dermatitis of the face
• Dermatomyositis
• Hypereosinophilia
• Hypothyroidism including myxedema coma
• Lymphedema
• Melkersson-Rosenthal syndrome (i.e. recurrent facial edema, fissured tongue, occasional facial nerve palsy)
• Superior vena cava syndrome
• Systemic lupus erythematosus
• Tumors of the head and neck

Because of the rapid onset, neoplasms and infections can usually be ruled out as a cause of the edema. Hematomas can also cause edema and can be diagnosed by their color, and cervicofacial emphysema,which can usually be diagnosed by the “crepitus” of the swollen tissues.

Learning Point
Acute intraoral leucoplakic lesions are most commonly caused by trauma that usually has a concomitant history and presents with an usually single, ill-defined painful area with a smooth surface and erythematous or white border. These are treated symptomatically with anesthetics and coating agents to relieve pain. Occasionally steroids are used to help ulcers heal faster. Most trauma heals in 7-10 days.

Intraoral lesions associated with leucoplakia that may present acutely includes:

• Trauma
  • Biting
  • Accidental trauma
  • Chemical injury
  • Electrical injury
• Infections
  • Bacterial
    • Acute necrotizing ulcerative gingivitis - associated with spirochetes and Prevotella intermedia
    • Streptococcus Group A
  • Viral
    • Coxsackie - Hand-foot-mouth disease, herpangina
    • Heck’s disease - viral induced multi-focal hyperplasia of the oral mucosa
    • Herpes - primary or secondary infection
    • Measles
    • Mumps
    • Varicella
  • Fungal
    • Candida
• Salivary gland dysfunction
  • Mucocoele
  • Ranula
• Other
  • Angioedema
  • Bohn’s nodules
  • Medications
  • Retained food

Questions for Further Discussion
1. What are the indications for an evaluation for hereditary angioedema?
2. What are the treatments available for angioedema?
3. What are the indications for consultation with dentistry for intraoral lesions?

Related Cases

Disease
Angioedema
Edema
Hives

Symptom/Presentation
Dental Problems
Edema
Facial Swelling

Specialty
Allergy / Pulmonary Diseases
Dentistry / Orthodontia

Age
School Ager

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Edema and Hives.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Baxi S, Dinakar C. Urticaria and angioedema. Immunol Allergy Clin North Am. 2005 May;25(2):353-67, vii.

Pintos A. Pediatric Soft Tissue Lesions. Dental Clinics of North America. 2005;241-258.

Krishnamurthy A, Naguwa SM, Gershwin ME. Pediatric angioedema. Clin Rev Allergy Immunol. 2008 Apr;34(2):250-9.

ACGME Competencies Highlighted by Case

Patient Presentation
A 6-year-old female came to a pediatric nephrologist with a 2-month history of intermittent rash. The rash was located bilaterally on the ankles and was described as initially red, papular and then became pustular with white fluid. It was not pruritic and the family denied any new contacts or ill exposures. The patient was seen locally by their regular physician who prescribed antibiotics. The rash resolved. The rash then returned and the patient was seen twice over the next month in a local emergency room. Again antibiotics were prescribed and the rash resolved. The patient returned for a third emergency room visit and the rash now was described as having a halo of bluish discoloration and was also seen on the buttocks and ankles bilaterally. The patient also had intermittent abdominal pain that lasted 1-2 days, resolved and returned over the past week. There was no change in stools or appetite. The parents report that sometime in the past month her urine had looked “different.” A urinalysis showed hematuria and proteinuria.

The past medical history was non-contributory.

The family history was negative for any gastrointestinal or nephrological problem. There was some hypertension in two grandparents.

The review of systems showed no change in stools or stooling pattern, fever, emesis, joint swelling, or difficulty ambulating.

The pertinent physical exam showed vital signs to be normal but with an elevated blood pressure of 110/65. Her weight was 23 kg but previous weights were not available. HEENT was negative except for mild periorbital edema. Abdominal examination showed a slightly protuberant abdomen without a fluid wave or masses. Extremities showed mild ankle edema with palpable ~3 mm bluish-red lesions around the ankle and intermittently up the posterior legs to the buttocks. These lesions were non-blanching nor were pruritic. The rest of the examination was normal.

The laboratory evaluation included a normal complete blood count, coagulation profile, calcium, magnesium, phosphorus, alkaline phosphatase, electrolytes, albumin, total protein, and cholesterol. Urinalysis showed 3+ proteinuria and hematuria and a low C3 of 55 mg/dL (normal 90-180 mg/dL). C4 was normal.

The diagnosis of probable Henoch-Schönlein purpura (HSP) was made and the patient was begun on a course of steroids.

The patient’s clinical course over the next 2 weeks found her to be increasing in weight and developing more edema. She was admitted to the hospital for further management and evaluation as her symptoms had not improved. She received intravenous albumin, furosemide and solumedrol, which improved her blood pressure and clinical symptoms. As this patient had been on steroids and needed hospitalization and a solumedrol pulse, she underwent renal biopsy to determine if this was HSP, another vasculitic or an infectious/post-infectious process. The results were pending.

Discussion
Henoch-Schönlein purpura (HSP) is a generalized vasculitis that commonly involves the gastrointestinal tract, kidneys, skin and joints. It can also affect the lungs and central nervous system much less often. Its etiology is uncertain but is probably multifactorial with antigens, environmental and genetic factors. It is thought to be caused by an unknown antigen stimulating a rise in IgA producing and antigen-antibody complexes being deposited locally in the body and activating pathways leading to necrotizing vasculitis.

Most children with HSP are between 2-11 years old with males affected more than females in a 2:1 ratio. Most children have a preceding gastrointestinal, pharyngeal or upper respiratory tract infection. Associations with bacteria, viruses, vaccinations and drugs have been reported.

Signs and symptoms of HSP include:

• Headache, fever and malaise may occur as a prodrome.
• The rash of classic HSP is a non-blanching red-purple-rust colored macules or plaques. They may be urticarial and/or palpable. They are particularly found on the buttocks and lower extremities but can be found in other locations. It may occur in new crops or waves. It may come and go throughout the illness and it may come late in the presentation making the diagnosis more difficult.
• Migratory polyarthritis especially of the knees and ankles but other joints often occurs with pain and edema.
• Colicky abdominal pain often occurs with or without nausea and emesis. This can last for several weeks and is sometimes treated with steroids. Complications such as bowel perforation, gastrointestinal bleeding, and intussception can make the differential diagnosis of abdominal pain more difficult for patients with HSP.
• Renal involvement includes a wide range from mild hematuria and proteinuria to renal failure. Renal symptoms may persist for 6 months after the rash. Peripheral edema may also occur.

Most children have complete recovery but serious renal and gastrointestinal complications may occur.
Long term morbidity is mainly related to renal involvement.

Treatment is mainly supportive with close followup and monitoring of proteinuria and hematuria at intervals. Complications require more aggressive treatment.

Learning Point
Renal biopsy is sometimes necessary to more clearly differentiate other causes of acute/chronic renal failure in patients that appear to have HSP including:

• Anaphylactic purpura with nephritis
• Hemolytic-uremic syndrome
• IgA nephropathy
• Infectious glomerulonephritis - bacterial (especially post-streptococcal), viral and fungal etiologies
• Membranoproliferative glomerulonephritis
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Wegner’s granulomatosis

Questions for Further Discussion
1. What other diseases should be included in the differential diagnosis of HSP?
2. What are the differences between nephrotic syndrome and nephritis?
3. List the possible gastrointestinal complications of HSP.
4. When should steroids be used for HSP?

Related Cases

Disease
Henoch-Schönlein Purpura
Skin Diseases
Vasculitis

Symptom/Presentation
Abdominal Pain
Erythematous Maculopapular Lesions
Urine

Specialty
Dermatology
Gastroenterology
Nephrology / Urology

Age
School Ager

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Skin Conditions and Vasculitis.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Haroon M. Should children with Henoch-Schonlein purpura and abdominal pain be treated with steroids? Arch Dis Child. 2005 Nov;90(11):1196-8.

Dyne PL, Sawtelle S, Kesler D. Pediatrics, Henoch-Schonlein Purpura. eMedicine. Available from the Internet at http://emedicine.medscape.com/article/804681-overview (rev. 12/20/2007, cited 1/5/09).

Sanders JT, Wyatt RJ. IgA nephropathy and Henoch-Schönlein purpura nephritis. Curr Opin Pediatr. 2008 Apr;20(2):163-70.

ACGME Competencies Highlighted by Case

Patient Presentation
A 4-day-old male was transferred to a regional children’s hospital for direct hyperbilirubinemia.
The infant was full term, was discharged at 2 days of life, and returned that morning to his private medical doctor’s office for routine followup.
Mother reports that he had been breastfeeding sluggishly, was urinating well and had stools that were yellow-colored.
The past medical history showed a normal pregnancy and delivery.
The family history was negative for congenital, metabolic, or gastrointestinal abnormalities.
The review of systems was negative.
The pertinent physical exam showed a jaundiced infant with a slightly protuberant abdomen.
The vital signs and growth parameters were normal.
He was jaundiced over the entire body including the eyes and he had no prominent cutaneous abdominal vasculature.
His liver was palpable 2-3 cm below the right costal margin and there was no splenomegaly or obvious masses.
The laboratory evaluation showed a total bilirubin of 17.1 mg/dL with a direct bilirubin of 7.1 mg/dL.
The gamma-glutamyltransferase was elevated at 580 U/L (normal up to 94 U/L). Alanine aminotransferase was 46 (normal up to 35 U/L) and the aspartate aminotransferase was 87 (normal up to 35 U/L). Coagulation studies were normal.
He had a normal complete blood count, electrolytes, and neonatal screen.
Later blood and urine cultures were negative including for cytomegalovirus and toxoplasmosis.
Other testing was negative including a sweat test for cystic fibrosis, syphilis, hepatitis A and B and alpha-1-anti-trypsin levels.
The radiologic evaluation of an ultrasound of the right upper quadrant showed a small gallbladder and a normal intra and extrahepatic biliary tree, and hepatobiliary scan revealed no excretion of radiotracer into the biliary tree or bowel.
He had a liver biopsy that showed moderate to severe fibrosis with proliferation of the bile ducts that was compatible with the diagnosis of of biliary atresia.
The patient’s clinical course showed that he underwent a Kasai procedure (i.e. hepatoportal enterostomy) at 10 days of life. He had some hepatomegaly until 18 months of age which then resolved.
At 3 years of life he is doing well without hepatomegaly, jaundice or abnormal growth.

“02-09-09Figure70BiliaryAtresiaUS.jpg”
Figure 70 - Transverse ultrasound image of the liver at
the level of the main portal vein shows the liver and intrahepatic
and extrahepatic biliary tree to be unremarkable. The gall bladder
(not shown) was small and collapsed, although the patient had been
fasting for 12 hours before the exam.

“02-09-09Figure71BiliaryAtresiaHIDA.jpg”
Figure 71 - Serial images from a hepatobiliary scan
obtained up to 5 minutes after the injection of radiotracer show
prompt uptake of radiotracer by the liver but no excretion of
radiotracer into the biliary tree, gall bladder, or bowel.

“02-09-09Figure72BiliaryAtresiaHIDA24Hours.jpg”
Figure 72 - Delayed image from a hepatobiliary scan
obtained at 24 hours after injection of radiotracer again fails to
show excretion of radiotracer into the biliary tree, gall bladder, or
bowel. A diagnosis of biliary atresia was therefore made.

Discussion
Biliary atresia occurs in 1 in 5000 - 12,000 live births worldwide. Its cause is unknown.
Biliary atresia was universally fatal until the Kasai procedure was introduced. Liver transplantation can be used if the Kasai fails.
Patients that have surgery early (< 60 days old) and who have a lower bilirubin level after the Kasai procedure appear to have a much better long-term prognosis.

Learning Point
Direct or conjugated hyperbilirubinemia is defined as direct bilirubin > 2.0 mg/dL and is > 10% of the total bilirubin.
Age at presentation, appearing well or ill, and other associated signs such as hepatomegaly or elevated gamma-glutamyltransferase can assist in the prioritization of the differential diagnosis.

The differential diagnosis of direct hyperbilirubinemia includes:

• Structural abnormalities
  • Alagille syndrome
  • Biliary atresia
  • Choledochal cyst
  • Gallstones
• Genetic/Metabolic abnormalities
  • Alpha-1-anti-trypsin deficiency
  • Cystic fibrosis
  • Fructose intolerance
  • Galactosemia
  • Glycogen storage disease
  • Gaucher’s disease
  • Niemann Pick
  • Neonatal hemochromatosis
  • Porphyria
  • Tyrosinemia
  • Wolman disease
• Infectious diseases
  • Intrauterine infection
  • Urinary tract infection
  • Sepsis
  • Adenovirus
  • Coxsackie virus
  • Cytomegalovirus
  • Hepatitis B
  • Herpes
  • Listeriosis
  • Rubella
  • Syphilis
  • Toxoplasmosis
• Other
  • Autoimmune hepatitis
  • Bile plug syndrome
  • Dubin-Johnson syndrome
  • Rotor syndrome
  • Hypopituitarism
  • Hypothyroidism
  • Idiopathic neonatal/giant cell hepatitis
  • Total parenteral nutrition

To review the differential diagnosis of indirect or unconjugated hyperbilirubinemia see What is the Differential Diagnosis of Neonatal Unconjugated Hyperbilirubinemia?

Questions for Further Discussion
1. What evaluation should be considered in an infant with direct hyperbilirubinemia?
2. What causes chronic hepatitis in a child?

3. What are the indications for liver transplantation?

Related Cases

Disease
Biliary Atresia
Bile Duct Diseases
Jaundice
Liver Diseases

Symptom/Presentation
Jaundice

Specialty
Gastroenterology
Neonatology
Radiology / Nuclear Medicine / Radiation Oncology
Surgery

Age
Newborn

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Bile Duct Diseases and Jaundice and at Pediatric Common Questions, Quick Answers for this topic: Jaundice

.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Illingworth RS. Common Symptoms of Disease in Children. Blackwell Scientific Publications: Oxford. 1988:127-35.

Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:1479.

Kirk JM. Neonatal jaundice: a critical review of the role and practice of bilirubin analysis.
Ann Clin Biochem. 2008:Sep;45(Pt 5):452-62.

Roach JP, Bruny JL. Advances in the understanding and treatment of biliary atresia.
Curr Opin Pediatr. 2008:Jun;20(3):315-9.

ACGME Competencies Highlighted by Case

Patient Presentation
A 10-year-old male came went to his private medical doctor’s office with a sore throat.
He was noted to have very large tonsils and was placed on clindamycin and prednisone.
A few days later he developed a low-grade fever. He was seen again and referred to an otolaryngologist for large tonsils and a tonsillectomy and adenoidectomy were performed that day.
He continued to be febrile with a sore throat and several days later went to the local emergency room where laboratory testing revealed markedly elevated liver function tests.
He was transferred to a regional children’s hospital for further evaluation.
The past medical history revealed a healthy child who was diagnosed with an Epstein-Barr infection 2 years previously based upon a positive monospot test.
The family history was non-contributory.
The review of systems was positive for fatigue and jaundice.
The pertinent physical exam showed normal vital signs except for a fever to 100.6° F.
He had scleral icterus and a yellow hue to his skin.
HEENT exam showed cervical lymph nodes that were < 0.5 cm in size bilaterally. Pharyngeal erythema was noted along with bilateral eschar in the tonsillar vaults.
Heart and lung examination were normal.
Abdominal examination revealed a liver 4 cm below the right costal margin that was firm with no obvious splenomegaly or masses.
Neurological examination showed a male who was very sleepy but arousable and aware of his surroundings and situation.
He had bilateral asterixis of his ankles.
An extensive laboratory evaluation and work-up was completed.
The pathological examination of the tonsils and adenoids, a bone marrow biopsy and a liver biopsy were all compatible with
the diagnosis of acute Epstein-Barr virus infection causing hemophagocytic lymphohistiocytosis.
Chemotherapy was begun and the patient began responding to treatment.

Discussion
Almost all humans are infected with Epstein Barr virus by adulthood.
After infection, EBV’s viral genome is retained in a small fraction of B lymphocytes for the patient’s lifetime.
Carriers who are healthy have ~1-50 infected cells per million leukocytes. The virus tends to stay in the cellular cytoplasm and does not express many proteins.
Patients who appear to have EBV-induced disease have a much higher viral loads and the viral-infected cells express many proteins which appear to lead to disease.
The major EBV strains are types A and B. EBV is associated with oncogenicity (particularly lymphomas and carcinomas), drug resistance and other diseases.
Patient

Learning Point
A monospot is a test for heterophil antibody agglutination of red blood cells of animals.
Timing is important for the test.
Positive testing appears usually within 1 week of the onset of symptoms with a peak at 2-5 weeks and then waning usually over 3 months.
Waning can occur for as much as 1 year.
During week 1 after symptoms begin, there is a 25% false negative rate. During week 2, there is a 5-10% false negative rate. By week 3 there is a 5% false negative rate.
Age is also important for the test. Young children and the elderly often will be falsely negative.

Other testing for Epstein Barr virus is available including indirect fluorescent antibody testing or enzyme linked immunosorbent assays. These are often more difficult to perform and are costlier. In-situ hybridization is also available for various biopsy specimens.

False positive causes for Monospot tests include:

• Laboratory error (the most common cause)
• Infectious
  • Cytomegalovirus
  • Hepatitis
  • Influenza
  • Malaria
  • Rubella
  • Varicella
• Leukemia/Lymphoma (especially Burkitt’s lymphoma)
• Pancreatic cancer
• Rheumatoid arthritis
• Serum sickness
• Systemic lupus erythematosus

Questions for Further Discussion
1. What are other viral causes of hemophagocytic lymphohistiocytosis?
2. What specific cancer types are associated with Epstein-Barr virus?

Related Cases

Disease
Epstein Barr Virus
Infectious Diseases
Infectious Mononucleosis
Cancer
Lymphatic Diseases

Symptom/Presentation
Abnormal Laboratory Test
Fever and Fever of Unknown Origin
Sore Throat

Specialty
Infectious Diseases
Oncology
Otolaryngology
Pathology

Age
School Ager

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Infectious Mononucleosis.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Bakerman’s ABC’s of Interpretive Laboratory Data. 4th Edit. Interpretive Laboratory Data Inc. Scottsdale, AZ. 2002: 387-388.

Gulley ML, Tang W. Laboratory Assays for Epstein-Barr Virus-Related Disease.
J Mol Diagn. 2008 Jul;10(4):279-92.

Moses S. Monospot. FamilyPracticeNotebook.com.
Available from the Internet at http://www.fpnotebook.com/ID/Lab/Mnspt.htm (rev. 11/32008, cited 12/8/08).

ACGME Competencies Highlighted by Case