Patient Presentation
A 2-year-old female came to clinic for a second opinion. She was managed by a tertiary medical center in another state and the parents were happy with the care they received but wanted another opinion about diagnosis and overall management. After an uneventful pregnancy and delivery she was noted to be losing weight at her 2 month appointment. Nutritional supplementation and medication for gastroesophageal reflux disease was begun. At 5 months, her length was also falling behind, and she was hospitalized for pneumonia. A swallow study showed dysphagia and aspiration. Nasogastric feeds (later gastric tube feeds) were begun and continue to the present although she does take thickened foods. Over her lifetime, she had developmental delay but no developmental regression and poor muscle tone. She was receiving occupational therapy, physical therapy and speech therapy. A brain magnetic resonance imaging study was negative, cardiology evaluation showed a benign flow murmur, and a genetics consultation showed no obvious chromosomal abnormalities and an initial metabolic screening was normal. Multiple endocrinologic and other laboratory testing has been negative. Two months ago the family did try to wean her off her feeds but she lost weight. At a routine followup appointment, her local pediatrician noted splenomegaly but no hepatomegaly and re-referred her to the geneticist. An ultrasound examination confirmed the splenomegaly with slight enlargement of the liver but which did not meet criteria for hepatomegaly. The parents said that they were told that a urine test was abnormal but that they had to wait for more testing and had a followup appointment in 2 weeks. Later during the evaluation the mother found a torn paper in her purse that she had written when she had spoken with her doctor. The words “aminoglycan” and “sugar” were readable. The review of systems showed her wearing glasses. The pertinent physical exam shows a cooperative female with symmetric growth retardation consistent with the 50% for an 18 month old. Her head was 10% for her chronological age. Her facies are somewhat full with coarsening of the eyebrows. Abdominal examination shows a soft, non-tender abdomen with an intact G-tube button in place. There is no hepatomegaly, but the spleen is palpable 3-4 cm below the left costal margin and especially prominent in the left flank. Neurologically she is hypotonic and sits in a wide-based Indian-style position with tripoding of her arms. Her strength is normal.

The diagnosis of a child with a probable, currently undiagnosed, infiltrative genetic disease was made. The pediatrician said that although he wasn’t sure what the disease was, that it appears from the records available and the history and diagnosis that this was possibly a lysosomal storage disease or a mucopolysaccaridosis. He wrote these down for the parents but cautioned that the geneticist would be the best person to order appropriate tests and interpret them. He also re-assured the family that although it is difficult not to have a diagnosis, it appears that one maybe made soon and that the child seemed to be doing well with the treatment plans in place at their current medical center. The family re-iterated that they were happy with their current plan and providers but “just wanted to make sure” and expressed relief that another person felt that they were providing good care to their child.

Discussion
Second opinions can often be tricky as there are numerous reasons for the consultation. Often a healthcare provider will send a patient to confirm, deny or interpret a finding, e.g. a possible abnormal growth pattern in an infant. There may be a chronic problem that isn’t responding to the 2nd, 3rd or 4th line treatment, e.g. constipation. Maybe it is an ill-defined problem that despite appropriate evaluation, treatment and time, is not improving, e.g. fatigue. Communication issues often complicate the matter. Perhaps the healthcare provider may not adequately explain the problem to the family, or the family is not adequately listening or understanding the provider. There is always someone – patient, family member or health care provider – who truly has a question that they want answered, or is not able to adequately communicate about it (often both) and therefore this uncertainty can cause anxiety for the family and/or the provider.

Learning Point
The spleen has several functions including clearing defective red blood cells and their inclusions, clearing bacteria, serving as a reservoir for platelets and as a factory for extramedullary hematopoiesis if necessary. The spleen can be enlarged in up to 30% of newborns and 10% of children. Generally it is less than 1 cm below the left costal margin.

The differential diagnosis of splenomegaly includes:

• Congestion – cirrhosis, hepatic fibrosis, portal vein thrombosis, splenic vein thrombosis, long-standing congestive heart failure
• Extramedullary hematopoiesis – osteopetrosis, myelofibrosis, thalassemia major
• Hyperfunction – hemolytic anemia, hemoglobinopathies
• Infection – bacteria, cytomegalovirus, Epstein-Barr virus, brucellosis, malaria, schistosomiasis, toxoplasmosis, fungal diseases
• Infiltration and storage – glycogen storage disease, lipodosis, mucopolysaccaridosis, histiocytoses, sarcoid
• Neoplasm – leukemia, lymphoma, histiocytosis, neuroblastoma
• Benign lesions – hemangiomas, splenic cysts
• Systemic disease – systemic lupus erythematosus

Questions for Further Discussion
1. What are the potential complications of splenomegaly?
2. What are potential indications for splenectomy?
3. When can a child with splenomegaly secondary to Epstin-Barr virus return to athletic competition?

Related Cases

Disease: Metabolic Disorders

Symptom/Presentation: Lymphadenitis | Mass or Swelling | Abdominal Mass

Specialty: Developmental Disabilities | General Pediatrics | Genetics

Age: Toddler

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 this topic: Metabolic Disorders

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

To view images related to this topic check Google Images.

Kainth MK, Kanwar VS, Sills RH. Splenomegaly. eMedicine.
Available from the Internet at http://emedicine.medscape.com/article/958739-overview (rev. 9/4/2008, cited 3/24/2010).

Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:1561.

ACGME Competencies Highlighted by Case

Patient Presentation
A 9-year-old female came to clinic for a second opinion for continued fevers. She had a 3 month history of episodes of fever up to 103° F. that would last 2-4 days, almost always associated with respiratory symptoms. These episodes originally occurred every 2-3 weeks, but she had an episode one week ago and this week has a similar episode. The current episode is also accompanied by moderate generalized headache and muscle aches. The fevers and other symptoms are well controlled with antipyretics. She is kept out of school because of the fevers and the parents are concerned. The patient has been diagnosed with otitis media and streptococcal pharyngitis clinically. The referring physician was worried because now the patient had headaches along with the fever and thought that maybe she had a periodic fever. Laboratory testing including a complete blood count, electrolytes, rapid streptococcal test, Monospot, urinalysis and chest radiograph were negative. The past medical history shows several episodes of otitis media, and influenza 2 years ago. There have been no hospitalizations or unusual infections. The social history shows that the patient had been home schooled until this year, and lives with 2 older brothers and her parents. There was no travel history, or exposure to people in the military, institutional settings or who were homeless. She drinks city water. The family history reveals migraine headaches that begin in childhood. Her older brother began his at 9-10 years. There was no history of other family members with unusual infectious diseases, problems with fever, or autoimmune diseases other than diabetes in overweight individuals. The family was of northern European descent. An extensive review of systems was negative.

The pertinent physical exam shows a slightly tired female with a temperature of 101° F. The rest of her vital signs are normal and the growth charts reveal normal growth including a 2 pound weight gain since a health supervision visit 5 months ago. HEENT examination showed copious clear rhinorrhea, erythematous pharynx without exudates, and shoddy anterior cervical adenopathy. She had mild tenderness of the head without photophobia or phonophobia. Her lungs were clear and her musculoskeletal examination revealed generalized mild myositis. The rest of her examination was negative. The diagnosis of recurrent fevers most consistent with recurrent viral infections was made, given the fever pattern. The current illness was most consistent with influenza that was currently circulating in the community. As the child had not been in a school-type setting before, viral infections were the most likely cause and this was explained to the family. The parents continued to be anxious about the fevers but were somewhat relieved. The pediatrician developed a plan with the family and local physician to monitor the patient, gather additional symptom data and reassess the patient in a month, with the caveat that if other more serious symptoms developed then the patient would be evaluated at that time and possibly additional testing completed.

Discussion
Fevers that are perceived by patients, families and health care providers as not following a “normal” pattern bother everyone. Patients and families may have different expectations than healthcare providers about the actual temperature measurement, duration of the fever, and other assorted factors such as where the temperature was taken, the instrument used and whether antipyretic medication had been used. Luckily for most patients, fever, even true recurrent fevers, are often self-limited and have good prognoses.

Fever patterns include:

• Recurrent fever
  • Multiple episodes that occur at inconsistent intervals involving multiple organ systems, fever is one component
  • Multiple episodes that occur at inconsistent intervals involving a single organ system
  • Single episode where signs, including fever, wax and wane
• Prolonged fever
  • Single episode where the fever is longer than expected for the clinical diagnosis (for example, viral syndrome lasting > 10 days)
  • Single episode where fever initially was a major symptom and then becomes low grade or is only believed to be a problem by the family.
• Fever of Unknown Origin
  • Single episode of more than 3 weeks duration where fever (>38.3) occurs on most days. After 1 week of evaluation diagnosis must also be uncertain.
• Periodic fever
  • Multiple recurring episodes that occur with regular periodicity or inconsistently, where fever is main feature and where other signs/symptoms are consistent and predictable. Duration of symptoms is days to weeks. Respiratory symptoms are not present.

Learning Point
Patients with true periodic fevers develop a more predictable pattern of fever and illness overtime. Therefore it can be difficult early in the course of the illnesses to know if this is the first presentation of the periodic fever. Periodic fevers often will have an abrupt onset and cessation with fever being the main feature, and there are no respiratory symptoms. Each episode is basically identical with regards to symptoms and their course throughout the episode. The patient is also well between the episodes, and the episodes may occur with a regular periodicity or be inconsistent with their timing. The family history may show family members with similar symptoms or autoimmune illnesses. Periodic fevers also are more common in certain groups genetically:

• Blau syndrome
  • Cause – autosomal dominant, chromosome 16
  • Fever with arthritis, iritis, and skin rash
• Cyclic neutropenia
  • Cause – enzyme defect, autosomal dominant, chromosome 19
  • Fevers, pharyngitis, lymphadenopathy and mouth ulcers
• Familial Mediterranean Fever
  • Cause – protein defect, autosomal recessive, chromosome 16
  • Fever and pain (especially abdominal, pleura, pericardium, scrotum, joints, muscle)
• FCAS/FCUS syndrome
  • Familial cold autoinflammatory syndrome/familial cold urticaria syndrome
  • Cause – autosomal dominant , chromosome 1
  • Fever, arthralgia and rash
• HIDS
  • Hyperimmunoglobulinemia D and periodic fever syndrome
  • Cause – enzyme defect, autosomal recessive, chromosome 12
  • Fever, abdominal pain, joint pain, diarrhea, hepatosplenomegaly, lymphadenopathy, and skin lesions
• Muckle-Wells syndrome
  • Cause – autosomal dominant, chromosome 1
  • Fever, amyloidosis, deafness, and urticaria
• NOMIC/CINCA syndrome
  • Neonatal-onset multisystem inflammatory disease/chronic infantile neurologic cutaneous and articular syndrome
  • Cause – autosomal dominant, chromosome 1
  • Fever, arthropahy, meningitis, rash
• PFAPA syndrome
  • Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy
  • Cause unknown
• PAPA syndrome
  • Pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome
  • Cause – autosomal dominant, chromsome 15
• TRAPS
  • Tumor necrosis factor receptor-associated periodic syndrome
  • Cause – protein defect, autosomal recessive, chromosome 12
  • Fever, abdominal pain, painful skin lesions and myalgia

Questions for Further Discussion
1. What is the purpose of laboratory testing in fever syndromes?
2. What laboratory testing would you do for recurrent fevers, prolonged fevers or a fever of unknown origin?

Related Cases

Disease: Influenza | Common Cold

Symptom/Presentation: Fever and Fever of Unknown Origin | Headaches | Pain | Rhinitis

Specialty: General Pediatrics | Genetics | Immunology |Infectious Diseases

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: Flu and Common Cold and at Pediatric Common Questions, Quick Answers for this topic: Flu

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

To view images related to this topic check Google Images.

Padeh S. Periodic fever syndromes.
Pediatr Clin North Am. 2005 Apr;52(2):577-609, vii.

Long SS. Distinguishing among prolonged, recurrent, and periodic fever syndromes: approach of a pediatric infectious diseases subspecialist.
Pediatr Clin North Am. 2005 Jun;52(3):811-35, vii.

Online Mendelian Inheritance in Man. Blau Syndreme.
Available from the Internet at http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=186580 (rev. 6/2/2009, cited 2/18/2010).

Goldfinger, SE. PAPA Syndrome. Merck Manual.
Available from the Internet at http://www.merck.com/mmpe/sec19/ch297/ch297f.html (rev. 1/2009, cited 2/18/2010).

ACGME Competencies Highlighted by Case

Patient Presentation
A 3-year-old male came back to clinic for an increasing number of skin lesions. He had been diagnosed by another of the practice’s partners with urticaria pigmentosa 9 months previously. Over the past 2-3 weeks his mother had noted more lesions, although some of them blistered and went away, and the antihistamines that he was taking were less effective. He was waking more at night because of pruritis and was fussier during the day. The past medical and family histories was non-contributory. The review of systems showed no specific fever, flushing, diarrhea, emesis, pain, respiratory problems or syncope.

The pertinent physical exam showed a healthy appearing male who was itching his right arm. His vital signs were normal and his growth parameters were 75-90%. His skin examination showed scattered, non-clustered, 3-7 mm, non-papular brown macules under his chin, at the hair line, trunk, extremities and also one on the right foot sole. Mother noted that the new lesions were under the chin, hair line and on the foot. These seemed to bother him the most per mother’s report. The patient had a wheal and flare reaction when one lesion was stroked. Dermatographism was not seen. The diagnosis of urticaria pigmentosa was made. The patient hadn’t been taking his non-sedating antihistamine daily and this was reinstituted, along with a sedating antihistamine. A consultation to the dermatologist for more aggressive management was made. An Epi-pen® (epinephrine) was also given with proper instructions as a precaution because the patient’s symptoms seemed to be increasing and it was unclear if this could represent a presentation of systemic mastocytosis versus only non-compliance.

Figure 81 – Clinical image of the rash of urticaria pigmentosa on the trunk. Other images can also be viewed in the To Learn More section below.

Discussion
Urticaria pigmentosa (UP) is one of the cutaneous forms of mastocytosis. Patients can present at birth and 80% of pediatric patients present by age 1, with both genders equally affected. Classical UP lesions in children are more hyperpigmented but may be erythematous, are 5 mm mean diameter and well demarcated. The distribution includes the trunk especially but face, scalp and other areas can be affected. Lesions may be flat or papular and may blister. The blisters resolve without scarring and these episodes usually remit by age 3. Darier’s sign (stroking of a lesion creating a wheal and flare response) is usually positive in patients not taking antihistamines. Dermatographism is usually not seen. Other forms of UP include plaque-like lesions, and nodular lesions, while others are erythematous and telangiectatic. Fortunately most children and adults do well with the disease and most children remit by adolescence.

UP may be the first presentation of systemic mastocytosis so a history of other problems is important. Because mast cells release granules and other mediators such as histamine, leukotrienes, prostaglandins, platelet-activating factor and interleukins, other symptoms may occur and include:

• Allergic – anaphylaxis
• Cardiovascular – flushing, palpitations, syncope
• General – fatigue, fever, weight loss, night sweats, pain
• Gastrointestinal – abdominal pain, diarrhea, nausea and emesis
• Pulmonary – wheezing
• Neurology/Psychiatry – depression, inattention, irritability, poor memory, personality changes

Learning Point
For patients with mainly pruritis and wheals, which is most patients with UP, daily treatment with non-sedating H1 antihistamines usually works. Other options include adding a sedating H1 antihistamine, a H2 antihistamine (such as cimetidine) or a tricyclic antihistamine such as doxepin.

For any patient at risk for anaphylactic reactions, an emergency kit including epinephrine should be available at all times.
Treatment for mastocytosis includes:

• Avoidance of these triggers
  • Alcohol
  • Irritation of the skin
  • Insect stings – especially hymenoptera stings may have a more pronounced effect
  • Temperature extremes including sudden changes in temperature
  • Medication – non-steroidal anti-inflammatory medication, codeine, morphine, meperidine, general anesthesia, iodonated contrast media, and other drugs
• Increased awareness that these may increase the mast cell response
  • Food intake (but not specific foods)
  • Infection
  • Physical exercise
  • Stress
  • Specific triggers for the individual patient
• Medication
  • Antihistamines – prevent release of histamine
    • H1 antihistamine
    • H2 antihistamines
  • Cromolyn sodium – stabilize the mast cells
  • Glucocorticoids
  • Sunlight exposure
  • Surgical excision of the lesions
• Specific treatment for certain clinical presentations
  • Anticholinergics
  • Biphosphantes
  • Calcium and Vitamin D
  • Hormone treatment
  • Interferon
  • Leukotriene antagonist
  • Non-steroidal antiinflammatory drugs
  • Chemotherapy
  • Splenectomy
  • Bone marrow transplant

Questions for Further Discussion
1. What else is in the differential diagnosis of urticaria pigmentosa?
2. What counseling instructions do you give families regarding emergency epinephrine use?

Related Cases

Disease: Urticaria Pigmentosa | Itching | Skin Pigmentation Disorders

Symptom/Presentation: Non blistering, Nonerythemous Lesions | Urticaria and Pruritis

Specialty: Allergy / Pulmonary Diseases | Dermatology | Pharmacology / Toxicology | Radiology / Nuclear Medicine / Radiation Oncology

Age:
Preschooler

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: Itching and Skin Pigmentation Disorders.

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

To view images related to this topic check Google Images.

Brockow K. Urticaria pigmentosa.
Immunol Allergy Clin North Am. 2004 May;24(2):287-316, vii.

Shaffer HC, Parsons DJ, Peden DB, Morrell D. Recurrent syncope and anaphylaxis as presentation of systemic mastocytosis in a pediatric patient: case report and literature review.
J Am Acad Dermatol. 2006 May;54(5 Suppl):S210-3.

ACGME Competencies Highlighted by Case

Patient Presentation
Two patients came to clinic for well child care. The first was a 7-year-old male former 25 week premature infant with unilateral grade II intraventricular hemorrhage (IVH). He had problems with speech, gross motor skills and mental health issues. He was not able to speak until 3 years of age, but could now be understood easily. He also was quite slow obtaining his gross motor skills and was described as “just a little clumsy now.” He had severe attentional issues and obsessive traits that were managed with medication and behavioral interventions. Additionally he had learning problems in reading and math, but was receiving special education and behavioral therapy at school and making appropriate progress. The second patient was a 89-day-old female former 24 week premature infant with bilateral grade III IVH. She continued to need supplemental oxygen and was noted to be somewhat stiff during her examination, but was gaining good weight.

The diagnosis of former premature infants with IVH was made. These patients caused the resident and staff pediatricians to discuss neurodevelopmental outcomes of premature infants. The staff pediatrician felt he didn’t know the most current data, so together they performed a PubMed literature search. They also queried the Vermont Oxford Network (VON) as they knew this was a neonatology research network. VON did not publish the data directly but did list their research publications.

Figure 80 – Two contiguous coronal ultrasound images of the brain showing the echogenic focus of right intraventricular hemorrhage grade II involving the right germinal matrix (top image) and then extending into the superior portion of the right lateral ventricle without ventricular dilation (bottom image). The echogenic substance filling the inferior portions of both lateral ventricles in the bottom image is the patient’s normal choroid plexus.

Discussion
With the advent of multiple new technologies and the birth and maturation of neonatology as a pediatric specialty has come dramatically improved outcomes for premature and full term neonates. Mortality has decreased and more children that previously would have died, now live. Decreasing birth weight and decreasing gestational age are predictors of potential chronic neurodevelopmental problems. Other problems that premature infants face include retinopathy of prematurity, anemia, sepsis, necrotizing enterocolitis, pulmonary hypertension, and therapies such as oxygen and ototoxic drugs that are necessary for survival but that put the infant at increased risk for chronic morbidities. The infant central nervous system is particularly vulnerable and premature infants are at risk for intraventricular hemorrhage. There are 4 grades with higher numbers involving more of the brain and carrying a higher risk for morbidities. IVH grading can be reviewed here.

Learning Point
As there are many variables for survival and morbidity it is sometimes difficult to compare various research studies to determine what are the long-term neurological outcomes for premature infants with IVH.

A 2008 study of teenage patients who previously had grade IV IVH and porencephaly (N=10) found that all patients had impairments in motor skills, cognition and overall functioning. Most were ambulatory, and needed special education assistance and had social impairments.

A 2009 study of 12 year olds with previous grade III and IV IVH found that their intelligence quotient was 6-14 points lower than a control group of former premature infants without IVH, and both premature groups with and without IVH had lower intelligence quotient than full-term controls. Patients with IVH needed more school services in reading, writing and math when compared to premature controls and full term controls.

Another 2009 study of patients between 4-12 years of age with previous IVH found decreased intelligence quotients (mean of 83), abnormal behavior (47%) and abnormal executive functions (between 35-71% depending on parent or teacher report).

These data can only give a gestalt of the outcomes of premature infants with IVH. They also do not judge quality of life of the former premature infant.

Questions for Further Discussion
1. What is the current infant mortality in the United States and other countries?
2. What community and special education services are available for former premature infants in your community?
3. Where can families go to understand special education services and laws in your state?

Related Cases

Disease: Premature Babies | Developmental Disabilities

Symptom/Presentation: Behavior Problems | Developmental Delay | Health Maintenance and Disease Prevention | Learning Problems

Specialty: Developmental Disabilities | Neonatology | Psychiatry and Psychology | Radiology / Nuclear Medicine / Radiation Oncology | School

Age: Premature Newborn | 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: Premature Babies and Developmental Disabilities.

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

To view images related to this topic check Google Images.

Sherlock RL, Synnes AR, Grunau RE, Holsti L, Hubber-Richard P, Johannesen D, Whitfield MF.
Long-term outcome after neonatal intraparenchymal echodensities with porencephaly.
Arch Dis Child Fetal Neonatal Ed. 2008 Mar;93(2):F127-31.

Luu TM, Ment LR, Schneider KC, Katz KH, Allan WC, Vohr BR.
Lasting effects of preterm birth and neonatal brain hemorrhage at 12 years of age. Pediatrics. 2009 Mar;123(3):1037-44.

Roze E, Van Braeckel KN, van der Veere CN, Maathuis CG, Martijn A, Bos AF.
Functional outcome at school age of preterm infants with periventricular hemorrhagic infarction. Pediatrics. 2009 Jun;123(6):1493-500.

ACGME Competencies Highlighted by Case