What is PAN?

Patient Presentation
An 18-year-old female came to clinic for her health supervision visit before leaving for college in another state.

Her past medical history showed she had had cutaneous polyarteritis nodosa (PAN) diagnosed at age 14 when she had some fever, myalgia and subcutaneous erythematous nodules along her bilateral shins. She had been managed by rheumatology with steroid medication and had achieved and remained in remission after being weaned off her medication.

The pertinent physical exam revealed a healthy female with normal vital signs and stable growth parameters.

The diagnosis of a healthy female in remission for cutaneous PAN was made. Her next rheumatology appointment was in 2 months. “You can always call your rheumatologist if you have any concerns while you are at college, but it probably is also good to have another rheumatologist already picked out if you need someone. I’m also here to help you so you can call me too,” the pediatrician explained.

Vasculitis is an inflammation of the blood vessels. Often, the term implies the arterial vessels, but venous and capillary vessels can be affected. The nomenclature to describe vasculitis and its classification have varied over time. Arterial vessel size is one method and some more common entities include:

  • Small vessel, mainly
    • Granulomatous – granulomatosis with polyangiitis (aka Wegener’s granulomatosis), eosinophilic granulomatosis with polyangiitis (aka Churg Strauss syndrome)
    • Nongranulomatous – Henoch-Schonlein purpura (HSP), microscopic polyangiitis
  • Medium vessel, mainly
    • Childhood systematic polyarteritis nodosa
    • Cutaneous polyarteritis nodosa
    • Kawasaki disease (KD)
  • Large vessel, mainly
    • Takayasu arteritis
  • Other
    • Bechet disease
    • Secondary due to infection, drug, and malignancy including Hepatitis-B-associated polyarteritis nodosa
    • Central nervous system vasculitis, isolated
    • Connective tissue disease associated vasculitis

Management and treatment can involve multiple specialists because of potential complications. Mainstays of treatment are glucocorticoids and anti-inflammatory medications.

Learning Point
Polyarteritis nodosa was first described in 1866 and “…is a necrotizing vasculitis associated with aneurysmal nodules along the walls of medium-sized muscular arteries…” It can also occur in small vessels. It is the third most common childhood systemic vasculitis after HSP and KD, but overall is relatively rare. Diagnosis is with evidence of necrotizing vasculitis in small or medium sized arteries on biopsy or abnormal angiographic findings such as aneurysm, occlusion or stenosis, plus other findings such as myalgia, hypertension or renal involvement or peripheral neuropathy. Clinical features can include:

  • Systemic – fever, malaise, pain (e.g. abdominal pain, arthralgia myalgia) and rash
  • Dermatological – variable – livido reticularis (net-like, red-blue skin discoloration to the skin that is relatively well demarcated), subcutaneous nodules (particularly in lower legs)
  • Gastrointestinal – peritoneal or retroperitoneal bleeding
  • Organic pain – ischemic heart pain, testicular pain
  • Neurological – focal defects, hemiplegia, visual loss, psychosis
  • Renal – hematuria, proteinuria, hypertension

The differential diagnosis includes HSP, KD, other vasculitides, connective tissue diseases, infections (e.g. subacute bacterial endocarditis) and malignancies. Antineutrophil cytoplasmic antibodies (ANCA) are negative and this helps to differentiate it from other vasculitides.

Cutaneous PAN is a necrotizing vasculitis of small and medium sized arteries but is limited to the skin. It can have systemic involvement such as fever, arthralgia, and myalgia but skin lesions predominate. Skin findings can include livido reticularis, and usually painful, subcutaneous non-purpuric lesions. The lower extremities are a common location. In children cutaneous PAN is associated with streptococcal infections and may recur with them. Cutaneous PAN has a high remission rate.

PAN and cutaneous PAN can be seen both in childhood and adults but adults are more common overall. One relatively large, registry study in France consisting of 21 children (<18 years) and 84 adults studied patients’ characteristics and outcomes. Children were slightly less likely to have systemic disease than adults but most comparisons were not statistically significant. Children also had shorter relapses than adults, but children were more likely than adults to have at least 1 flare than adults. Cumulative body damage and deaths were similar between the two groups.

Children with cutaneous PAN were statistically less likely to have myalgias and purpura, but were more likely to have skin nodules but this was not statically significant (92% versus 59%, p=0.06). Children with cutaneous PAN had the same relapse rates, and deaths as adults.

Questions for Further Discussion
1. What are the characteristics of HSP? A review can be found here
2. What are the characteristics of KD? A review can be found here
3. What are the characteristics of Bechet’s Disease? A review can be found here

Related Cases

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 and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Vasculitis

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

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Dillon MJ, Eleftheriou D, Brogan PA. Medium-size-vessel vasculitis. Pediatr Nephrol. 2010;25(9):1641-1652. doi:10.1007/s00467-009-1336-1

Ozen S. The changing face of polyarteritis nodosa and necrotizing vasculitis. Nat Rev Rheumatol. 2017;13(6):381-386. doi:10.1038/nrrheum.2017.68

Iudici M, Quartier P, Pagnoux C, et al. Childhood- versus Adult-Onset Polyarteritis Nodosa Results from the French Vasculitis Study Group Registry. Autoimmunity Reviews. 2018;17(10):984-989. doi:10.1016/j.autrev.2018.08.001

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

What Causes Mediastinal Masses?

Patient Presentation
A 14-year-old male was referred with a history of lymphadenopathy and anterior mediastinal mass. He had been well overall but had had some increased coughing and his mother noticed his neck looked larger. He was evaluated and referred for possible lymphoma or another oncological problem. He had a 3-pound weight loss and no fevers, sweats, rashes, nausea, emesis, bruising or bleeding.

The pertinent physical exam showed normal vital signs without fever. He had 3 anterior and posterior cervical lymph nodes that were quite firm but not adherent that measured 2-4 cm both in width and length. He had a superior clavicular node of 2 cm across on the right side. He also had several groin nodes of 1-2 cms but no axillary, tonsillar,or other nodes behind the knees or elbows and no hepatosplenomegaly.

The radiologic evaluation revealed an anterior mediastinal chest mass with characterization as below. The work-up included the laboratory evaluation which was essentially normal and lymph node biopsy was consistent with a diagnosis of nodular sclerosing Hodgkin’s lymphoma. The patient’s clinical course showed that he was started on chemotherapy and responded well. Two years later the patient was disease free.

Case Image

Figure 130. PA and lateral CXR (above) shows a large mass in the anterior mediastinum. CT with contrast of the chest (below) shows the mass to be primarily in the anterior mediastinum with some extension into the middle mediastinum. The mass is heterogeneous due to necrosis and is causing airway compression. There is a small right pleural effusion.

The mediastinum resides in the chest and is the space bounded by the thoracic inlet cephalically, diaphragm caudally, sternum anteriorly and transverse process of the spine posteriorly, and mediastinal pleura and lungs laterally. It is divided into various compartments:

  • Superior mediastinum
    • Bounded by the thoracic inlet cephalically and a horizontal plane passing from the manubriosternal joint to the junction of T4/T5 vertebrae horizontally.
    • Structures include: esophagus, trachea, parts of great vessels and first branches, great veins and initial branches, thymus, vagus, phrenic and other nerves, thoracic duct and lymph nodes
  • Inferior mediastinum
    • Bounded by the superior mediastinal compartment to the diaphragm caudally. It is divided into 3 main compartments anterior to posterior
      • Anterior (prevascular) compartment from the sternum to anterior heart border posteriorly. Structures include: thymus, lymph nodes and fat
      • Medial (visceral) compartment from the anterior compartment to 1 cm before the spinal vertebral body. Structures include: heart, parts of great vessels, pericardium, trachea and main bronchi, lymph nodes and phrenic nerve
      • Posterior (paravertebral) compartment from 1 cm before the spinal vertebral body through the chest to the transverse processes of the vertebral body. Structures include: some parts of vessels including descending aorta, azygous and hemiazygous veins, esophagus, thoracic duct, vagus and autonomic nerves

Hodgkin’s lymphoma accounts for 6% of childhood tumors and is most common in the 15-19 year old in the pediatric age range. The most common type is nodular sclerosing (40-45%) and mixed (30-45%). Epstein-Barr Virus has been associated with Hodgkin’s lymphoma but less commonly than in the adult population. Advanced stage disease occurs in 30-40% of childhood patients but 5-year survival rates are very high at 90+%.

Learning Point
Mediastinal masses can have significant effects because they take up potential space and impinge on critical structures. Maintaining a patent airway can be challenging and perfusion can be compromised by superior vena cava syndrome. Masses can originate in one compartment but extend to others with lymphatic malformations being a good example of this. Using the centering method, where the center of the mass is identified and then determining the mass effect on the surrounding structures, can help identify which compartment a large tumor is located in and assist with its differential diagnosis. Up to 35-50% of mediastinal masses in children are malignant. Age also helps with the differential as lymphoma is more likely to occur in older ages and neurogenic tumors are more common in younger ages.

    Anterior mediastinal masses count for approximately 30% of masses and are remembered by the 5T’s

    • Thymoma
    • Teratoma and other germ cell tumors
    • Thyroid (ectopic)
    • Terrible lymphoma both Hodgkin’s and non-Hodgkins which is the most common anterior mediastinal mass
    • Thymus, prominent such as thymic hyperplasia or cyst

    Middle mediastinal masses account for 30% of mediastinal masses and are remembered as A + B

    • Adenopathy caused by infection, granulomatous disease, or neoplasm
    • Aneursym of the left atrium or dilated vessel, and achalasia
    • Bronchopulmonary foregut malformation such as esophageal duplication, bronchogenic cyst, or pulmonary sequestration</ul
    • Posterior mediastinal masses account for 40% of mediastinal masses
      • Neurogenic or sympathetic ganglion tumors are 95% of posterior mediastinal masses including neuroblastoma, ganglioneuroblastoma or ganglioneuroma
      • Neurofibroma
      • Bronchopulmonary foregut malformation
      • Paraspinal abscess from diskitis or osteomyelitis
      • Extramedullary hematopoiesis
      • Dilated vessels

Other masses are less common such as vascular tumors, sarcomas, lymphatic malformations, ectopic parathyroid adenomas, pancreatic pseudocysts and solitary fibrous tumors.

Questions for Further Discussion
1. How do you evaluate lymphadenopathy?
2. What is the differential diagnosis of lymphadenopathy? A review can be found here.
3. What are the most common solid and hematopoietic tumors in children?
4. What are some presentation of Epstein Barr Virus? A review can be found here.

Related Cases

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 and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Hodgkin’s Lymphoma and Chest Injuries and Disorders.

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

To view radiological images related to this topic check PediatricImaging.org.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Jain S, Gupta A, Nagalla S. A Mediastinal Mass in a Young Man. JAMA. 2018;319(23):2432-2433. doi:10.1001/jama.2018.7107

Thacker PG. Magnetic resonance imaging of the pediatric mediastinum: updates, tips and tricks. Pediatr Radiol. 2022;52(2):323-333. doi:10.1007/s00247-021-05041-8

Sreedher G, Tadros SS, Janitz E. Pediatric mediastinal masses. Pediatr Radiol. 2022;52(10):1935-1947. doi:10.1007/s00247-022-05409-4

Childhood Hodgkin Lymphoma Treatment (PDQ)- Health Professional Version. Published October 14, 2022. Accessed November 28, 2022. https://www.cancer.gov/types/lymphoma/hp/child-hodgkin-treatment-pdq

Meconium: It Can Cause a Sticky Mess

Patient Presentation
A 2-day-old, term male was being seen in the newborn nursery. He was born to a G2P2 28-year-old female. There were no complications of pregnancy or vaginal delivery, after late second term prenatal care. He was breastfeeding well and had only lost 4% of his birthweight.

The pertinent physical exam showed a healthy male with weight of 3547 grams (75%), length of 50.5 cm (50%) and head circumference of 36.5 cm (75%).
He had some milia on his face, but was otherwise normal.

The diagnosis of a healthy male was made. Before rounding that day, his nurse informed the physicians that a meconium drug screen had been sent because the umbilical cord had been lost in transit to the laboratory. The physicians were surprised but upon further review, the mother’s chart noted that she had disclosed using marijuana as a teenager, and along with her later prenatal care, drug screening had been completed per hospital protocol. The patient’s clinical course showed he was discharged and at followup 2 days later was doing well. His weight was only 6% down from discharge and the mother was feeling well and supported by her family. The meconium drug screen laboratory evaluation eventually was normal.

During fetal life from approximately 12-13 weeks gestation, meconium accumulates in the small bowel and migrates to the large bowel and rectum by ~20 weeks gestation. Meconium is a combination of bile, mucous, desquamated intestinal cells, bowel secretions, dessicated swallowed amniotic fluid and lanugo. It is sterile before birth and once produced is odorless with a blackish green (sometimes brown or yellow) color, and tarry or sticky quality. Defecation does not occur during fetal life unless the fetus is significantly stressed. Normal meconium passage after birth occurs within 24-48 hours of life (more often within 24 hours). Delayed meconium passage begins an evaluation for anatomical obstruction (e.g. imperforate anus, colonic/rectal stenosis or atresia, mass effect, etc.), peristaltic problems (e.g. functional ileus, Hirschsprung disease) or intraluminal problems (e.g. cystic fibrosis) or other causes. Extreme prematurity also can have delayed passage of meconium as it is thought the normal intestinal musculature and/or innervation is also too immature to produce appropriate peristalsis and meconium movement. Imaging can be found here. Meconium’s tarry quality leads many parents commenting that they are happy once the stools transition and hygiene is easier to perform.

Learning Point
Meconium is normal and usually does not cause problems but they can be serious when they occur.

Meconium ileus is a neonatal intestinal obstruction problem caused by extremely thickened or inspissated meconium in the distal ileum. It is a very common first presentation of cystic fibrosis with ~20% of patient with cystic fibrosis present with it, but if it occurs almost 100% of patients have cystic fibrosis.. Complications of meconium ileus can include small bowel volvulus, bowel ischemia and/or necrosis, bowel perforation and possible meconium peritonitis and/or meconium pseudocyst formation. A broad differential diagnosis, where meconium ileus is only one possibility, or ileus and intestinal obstruction should to be considered and appropriately evaluated. Prenatal ultrasound can show meconium and meconium ileus appears as a hyperechoic bowel. Postnatally, plain radiographs show dilated loops of small bowel with or without air-fluid levels. Sometimes it may appear as “soap bubbles” when air mixes with the meconium. Contrast enemas will show a small or microcolon as the colon has not been used and therefore is not dilated to the normal expected size. Imaging can be found here and here. Management can include radiological and surgical procedures along with clinical management and support of the patient’s overall health. Distal intestinal obstruction syndrome is a fecal impaction in the distal ileum in patients with cystic fibrosis and is the child and adulthood equivalent of meconium ileus. It is common for patients with DIOS to have a history of meconium ileus. A review can be found here.

Meconium plug is caused by a functional colonic obstruction of retained meconium plugs with resultant small left colon often seen on radiographs. It is common in infants of diabetic mothers or mothers who received perinatal magnesium sulfate. Constrast enema shows multiple filling defects (the plugs) in the colon with a normal rectum. There may be a small left colon to the splenic flexure. Meconium passage is common after the procedure. Imaging can be found here.

Meconium aspiration syndrome (MAS) “is a clinical diagnosis what includes delivery through MSAF [meconium stained amniotic fluid] with respiratory distress with a characteristic appearance on chest radiograph and lack of an alternative diagnosis to explain respiratory distress.” Infants who are born through MSAF have been stressed and therefore are at risk for many problems including neonatal depression, birth asphyxia, respiratory distress, pand persistant pulmonary hypertension of the newborn. Infants born through MSAF are usually term or postterm and uncommon in premature infants unless there is prolonged rupture of membranes. In MAS, the meconium can cause chemical pneumonitis with surfactant dysfunction and inflammation and even physical airway obstruction. This can causes dead-space in the lungs, with resultant pulmonary vasoconstriction and pulmonary hypertension which causes right-to-left vascular shunting and resultant hypoxemia. Mitigation through use of infant suctioning at birth is standard but the exact procedure has changed overtime based on research studies. After delivery, respiratory support and/or mechanical ventilation may be necessary and ECMO (extra corporal membrane oxygenation) procedures sometimes are needed. ECMO treatment is less common in recent years as obstetrical intervention for the mother before becoming post-dates is more common. Imaging can be found here.

Drug testing can be completed using multiple body samples including urine (usual and preferred sample), saliva, sweat, hair and meconium. Meconium is the gold standard for detecting in utero drug exposure as it is non-invasive and has a large detection window including the second and third trimesters. Cons to meconium testing are that it can be contamined with urine, drugs given between birth and collection could be detected, there could be a limited sample and the sample needs more extensive extraction techniques to complete the testing.

Questions for Further Discussion
1. What are your hospital protocols for screening infants for potential maternal drug exposure?
2. What testing do you have available for drug testing at your institution?
3. What are some presentations for cystic fibrosis?

Related Cases

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 and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Childbirth Problems

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

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Jerdee T, Newman B, Rubesova E. Meconium in Perinatal Imaging: Associations and Clinical Significance. Seminars in Ultrasound, CT and MRI. 2015;36(2):161-177. doi:10.1053/j.sult.2015.01.007

Rawat M, Nangia S, Chandrasekharan P, Lakshminrusimha S. Approach to Infants Born Through Meconium Stained Amniotic Fluid: Evolution Based on Evidence? Amer J Perinatol. 2018;35(09):815-822. doi:10.1055/s-0037-1620269

Tamama K. Advances in drugs of abuse testing. Clin Chim Acta. 2021;514:40-47. doi:10.1016/j.cca.2020.12.010

Tobias J, Tillotson M, Maloney L, Fialkowski E. Meconium Ileus, Distal Intestinal Obstruction Syndrome, and Other Gastrointestinal Pathology in the Cystic Fibrosis Patient. Surgical Clinics of North America. 2022;102(5):873-882. doi:10.1016/j.suc.2022.07.016

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

What Laboratory Tests Are Consistent with Transient Erythroblastopenia of Childhood?

Patient Presentation
A resident in his pediatric continuity clinic curb-sided his attending pediatrician. “I saw a 15-month-old male this morning with one of the other attendings. He had a low hemoglobin and hematocrit when we tested him at 12 months and I started him on iron. He didn’t come back to check any labs and today I rechecked him. He’s still low for both and I’m not sure what to do next,” he asked.

“Iron deficiency anemia is still your most common cause. Do you think he even took the iron? Did his teeth look dark liked they were stained from the iron?” she asked.

“I’m not sure. But he looked well. No obvious bruising and mom didn’t complain of fatigue or bruising or bleeding. He should be absorbing the iron because he’s a healthy kid. He is Caucasian and didn’t have any weird hemoglobins on his newborn screen so I think a hemoglobinopathy is unlikely. I also think blood loss or hemolysis are also unlikely given his CBC today,” he answered.

‘I’m also going to assume that he had normal platelets and white blood cells and you aren’t worried about a malignancy, right?” she inquired.

“Yeah, platelets and white count are normal. His MCV is 83 so it is a little low but still a normocytic anemia,” he responded.

“Something else to consider is viral suppression. You should have more answers when the retics and iron studies come back later,” she added.

Later on that afternoon, the resident said that he had seen the other attending pediatrician who asked him to talk with the hematologist. He said the hematologist asked almost the same questions and added transient erythroblastopenia of childhood to the differential and also discussed next steps for other possible testing if the reticulocytes and iron studies didn’t support iron deficiency anemia.

The attending replied, “I sometimes forget about TEC as its one of those transient problems like viral suppression and gets better. That’s another one to add to the differential when we need to work up these kids. I still bet the mother didn’t give the iron though. The parents just often forget or the kid doesn’t like the taste,” she said.

Transient erythroblastopenia of childhood (TEC) is an “…anemia with a hemoglobin level at least 2 [standard deviations] below normal and a low reticulocyte count in relationship to the anemia in the absence of evidence of alternative causes of anemia.” A bone marrow aspirate shows decreased or absent erythroid precursor cells if obtained. The etiology is not well understood but may have a stimulating cause such as a viral infection, an immune-related and/or genetic cause. Parvovirus causing bone marrow suppression has been implicated and there are cases of affected siblings.

TEC is most common in 1-4 year olds but can be seen after 6 months and as old as 10 years. The natural history is that it spontaneously resolves usually in a few weeks (usually 4-8 weeks) but it can be for up to a year. Invariably as many patients only come to attention if they have severe disease and with normal spontaneous resolution, the actual number of TEC cases is probably underreported. Treatment is supportive including transfusion if the anemia is causing hemodynamic or other effects. Patients with more severe disease may have pallor, anorexia, lethargy and irritability, and most are hemodynamically stable. Treatment is supportive including transfusion if the anemia is causing hemodynamic instability or other effects.

Learning Point
TEC is often a clinical and laboratory diagnosis of exclusion if it follows its natural history.

Laboratory testing usually shows a normocytic anemia with very low reticulocytes (often < 0.1), and an increase in reticulocytes heralds the beginning of the recovery phase. White blood cells are usually normal but some patients will show a mild neutropenia. Platelet counts are also normal, but again could be slightly low. Mean corpuscular volume (MCV) of the red blood cells is normal. Iron studies are also normal. Other studies to consider in evaluations for anemia are evidence of blood loss (i.e. gastrointestinal, urinary), hemolysis, oncological problems, or viral-induced bone marrow suppression.

As TEC is a pure red cell aplasia, it seems to occur in the first year of life and must be distinguished from Diamond-Blackfan anemia (a congenital red cell aplasia). Other normocytic anemias include:

  • Blood loss
  • Hemolysis
  • Iron deficiency anemia, early
  • Anemia of chronic disease
  • Erythropoietin deficiency
  • Aplastic anemia – Schwachman-Diamond or Fanconi anemia
  • Myelodysplastic syndromes

Questions for Further Discussion
1. What are some congenital aplastic anemias? A review can be found here
2. Why is iron important to heme synthesis? A review can be found here
3. What are common hemoglobinopathies and how are they diagnosed?

Related Cases

    Disease: Transient Erythroblastopenia of Childhood | Anemia

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 and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Anemia

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

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Shaw J, Meeder R. Transient erythroblastopenia of childhood in siblings: case report and review of the literature. J Pediatr Hematol Oncol. 2007;29(9):659-660. doi:10.1097/MPH.0b013e31814684e9

van den Akker M, Dror Y, Odame I. Transient erythroblastopenia of childhood is an underdiagnosed and self-limiting disease. Acta Paediatrica. 2014;103(7):e288-e294. doi:10.1111/apa.12634

Burns RA, Woodward GA. Transient Erythroblastopenia of Childhood: A Review for the Pediatric Emergency Medicine Physician. Pediatr Emerg Care. 2019;35(3):237-240. doi:10.1097/PEC.0000000000001760

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa