The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire first by contacting Dr. Deepak Kamat at DKamat@med.wayne.edu.A 2-year-old boy with a history of eczema and food allergies to nuts and soy presents to the emergency department with a 10-day history of generalized edema. The swelling began in the periorbital area but soon progressed to involve his entire body. There have been no fevers or any recent illnesses other than 1 day of cough and a few watery stools. He has had no new exposures to foods or other substances. His family history is remarkable for multiple allergies and eczema.Physical examination reveals a temperature of 98.8°F (37.1oC), heart rate of 98 beats per minute, respiratory rate of 36 breaths per minute, blood pressure of 103/65 mm Hg, and an oxygen saturation of 97% on room air. His weight is 12.6 kg (34th percentile). He is noted to have a moderate amount of periorbital edema, decreased breath sounds at the lung bases bilaterally, a protuberant abdomen, and 2+ pitting edema on his lower extremities. The rest of his physical examination findings are within normal limits.Laboratory evaluation reveals a white blood cell count of 23,800/μL (23.8 × 109/L), with 37% neutrophils, 49% lymphocytes, 4% bands, 7% monocytes, and 3% eosinophils; hemoglobin level of 13.3 g/dL (133 g/L); and platelet count of 427 × 103/μL (427 × 109/L). Serum electrolyte, blood urea nitrogen, and creatinine levels are normal. Sodium level is 132 mEq/L (132 mmol/L). Serum albumin level is 1.7 g/dL (17 g/L) (reference range, 3.4-5.4 g/dL [34-54 g/L]). Total protein level is 3.8 g/dL (38 g/L). Aspartate aminotransferase, alanine aminotransferase, and coagulation profiles are within normal limits. The urinalysis result is negative for protein. The patient is hospitalized for further workup and management of his hypoalbuminemia and edema.An 8-year-old girl is evaluated in the emergency department for 6 days of high fevers. Her family reports nightly fever spikes to a temperature of 103.5°F (39.7°C) accompanied by frontal headache, chills, and myalgias. She reports decreased appetite, with 2 episodes of vomiting and 1 episode of diarrhea. She has had no cough, congestion, rhinorrhea, sore throat, abdominal pain, rash, joint pain or swelling, bruising, or bleeding. She has a history of asthma with no recent exacerbations. There is no history of travel or exposure to wooded areas. She has a pet kitten and turtle. One month ago, she went on a class trip to a petting zoo.On physical examination, she is not in acute distress. Her temperature is 103.5°F (39.7°C), heart rate is 140 beats per minute, and respiratory rate is 20 breaths per minute. Conjunctivae are clear, and funduscopic examination results are normal. Her lips are dry but not cracked or erythematous, and her oropharynx is benign. She has no neck stiffness. There is no palpable lymphadenopathy. There is no swelling of her joints and no rash. The remainder of her physical examination findings are normal.On laboratory evaluation her complete blood cell count, electrolyte, blood urea nitrogen, creatinine, and liver enzyme values are normal. Her erythrocyte sedimentation rate is 98 mm/h (reference range, 0-20 mm/h), and her C-reactive protein level is 17.06 mg/L (162.5 nmol/L) (reference range, 0.05-1.0 mg/L [0.48-9.5 nmol/L).She is hospitalized and continues to have daily spiking fevers. Her chest radiograph, abdominal ultrasonogram, head computed tomograph, and transthoracic echocardiogram findings are within normal limits. Chest, abdominal, and pelvis computed tomography reveals only a few enlarged right axillary lymph nodes. Additional laboratory evaluation reveals the cause of her fever.A 7-week-old girl is hospitalized for poor weight gain (13 oz since birth) and increased sleepiness for a few days along with recent onset of decreased formula intake. After hospitalization, she develops loose, nonbloody, yellowish brown stools and several episodes of nonbilious, projectile vomiting. The mother is a known carrier of hepatitis C and has a history of smoking and drug abuse. Various milk formulas had been tried in the past without much improvement in weight. History is also remarkable for one acute life-threatening event that was thought to be related to gastroesophageal reflux. The patient has no history of fever, rash, or seizures. Antenatal history is uncomplicated.On physical examination, all vital signs are normal for age. Her weight is 3.36 kg (5th to 10th percentile), head circumference is 36.4 cm (25th to 50th percentile), and length is 58 cm (25th to 50th percentile). On examination she is not interactive. Cardiovascular examination reveals a grade 2/6, soft, and nonradiating systolic murmur, best heard at the left sternal border. Neurologic examination reveals generalized hypotonia without any focal deficits. Other physical examination findings are normal.Laboratory values are as follows: white blood cells, 11,800/μL (11.8 × 109/L); hemoglobin, 10.5 g/dL (105 g/L); platelets, 410 × 103/μL (410 × 109/L); random blood glucose, 59 mg/dL (3.3 mmol/L) (reference range, 70-100 mg/dL [3.9-5.6 mmol/L]); aspartate aminotransferase, 293 U/L (reference range, 0-120 U/L); alanine aminotransferase, 209 U/L (reference range, 2-45 U/L); total bilirubin, 2.1 mg/dL (35.9 μmol/L) (reference range, 0.2-1.2 mg/dL [3.4-20.5 μmol/L]); activated partial thromboplastin time, 54.6 seconds (reference range, 25-35 seconds); γ-glutamyltransferase, 334 U/L (reference range, 0-35 U/L); ammonia, 104 μg/dL (74 μmol/L) (reference range, 18-52 μg/dL [13-37 μmol/L]); pyruvate, 0.22 mg/dL (25 μmol/L) (reference range, 0.30-1.50 mg/dL [34-170 μmol/L]); and lactate, 69.4 mg/dL (7.7 mmol/L) (reference range, 1.8-16.2 mg/dL [0.2-1.8 mmol/L]). Arterial blood gas and electrolyte values are normal. The patient is positive for hepatitis C antibody but negative for hepatitis C RNA quantitative viral load. Abdominal ultrasonography reveals diffuse increase in liver echogenicity. Additional studies reveal the diagnosis.The gastroenterology service was consulted, and further workup for a protein-losing enteropathy was initiated. A chest radiograph revealed bilateral pleural effusions, and an abdominal ultrasonogram confirmed ascites. An echocardiogram revealed a mild pericardial effusion. Further workup revealed an elevated fecal α1-antitrypsin level of 20.5 mg/g (3.8 μmol/L) (reference range, 0-1 mg/g [0-0.2 μmol/L]). The patient underwent esophagogastroduodenoscopy with biopsies that revealed hypertrophic gastric rugae consistent with Ménétrier disease. Cytomegalovirus (CMV) quantitative polymerase chain reaction (PCR) from the blood came back at 21,555 copies/mL. The result of the CMV PCR from the gastric tissue was positive as well. He received 2 infusions of 1 g/kg of 25% albumin, and his edema improved during the next 4 days. His tachypnea resolved, and he was discharged home; his albumin level at the time was 2.7 mg/dL (27 g/L). He was followed up in the gastroenterology clinic 3 weeks later and was noted to be doing clinically well without any further edema of his face, abdomen, or extremities. His serum albumin levels were within normal limits as well.Ménétrier disease, also known as protein-losing hypertrophic gastropathy, is a rare acquired condition of the stomach. The pathogenesis of the disease is not well understood but is thought to involve increased signaling of the epidermal growth factor receptor (EGFR), which results in proliferation of mucosal epithelial cells mainly in the body and fundus of the stomach perhaps through an overexpression of transforming growth factor α. These cells replace the normal chief and parietal cells, leading to excessive mucous production with little acid secretion. Patients develop edema secondary to hypoalbuminemia due to protein leakage through the gastric mucosa.Patients with Ménétrier disease often present with epigastric pain, anorexia, vomiting, diarrhea, and edema. They can develop additional clinical features, such as ascites and pleural and pericardial effusions. Laboratory abnormalities typically reveal hypoalbuminemia without proteinuria, malabsorption of fat and fat-soluble vitamins, and reduced plasma concentrations of γ-globulins, cholesterol, α1-antitrypsin, and fibrinogen.One-third of cases that involved children with Ménétrier disease are thought to be due to or associated with CMV infection; a few cases have been associated with Helicobacter pylori infection. It has been postulated that CMV infection leads to increased signaling of the EGFR. As the CMV virus is cleared from the system, the stimulus to the EGFR decreases, resulting in lessened cell proliferation of gastric mucosal epithelial cells and a return to normal anatomy. Thus, CMV-associated Ménétrier disease spontaneously resolves in 2 to 4 weeks in immunocompetent children.When the diagnosis of protein-losing enteropathy is established, the clinician should consider the following differential diagnoses: milk protein allergy, celiac disease, inflammatory bowel disease, giardiasis, intestinal lymphangiectasia, right-sided heart dysfunction (after the Fontan procedure), and hypertrophic gastritis (Ménétrier disease). The diagnosis of Ménétrier disease is established by the presence of enlarged gastric rugae seen on barium radiologic studies or endoscopy and by histologic confirmation. Serologic testing for CMV should also be considered, but detection of CMV DNA in a gastric biopsy sample by PCR is a more sensitive assay for confirming a possible cause.In adults, Ménétrier disease is often progressive. However, in children the process is usually self-limiting and resolves spontaneously within a few weeks. Close follow-up is highly recommended to monitor these patients for reduction of symptoms and an increase in serum protein levels. Severe cases may require intravenous albumin infusions. Oral proton pump inhibitors or histamine2-receptor blockers can also be used to treat gastric inflammation.Immunocompetent children with CMV-associated Ménétrier disease also have a self-limiting course that typically resolves in 2 to 4 weeks without any therapy. Treatment with ganciclovir should be considered in immunocompromised hosts and neonates who have an immature immune system or healthy infants who do not improve with supportive therapy. Testing for H pylori should be considered because coinfection with CMV and H pylori has been reported in the literature.Other medical treatments being studied in Ménétrier disease include the use of octreotide (a somatostatin analogue) and cetuximab (a monoclonal antibody to EFGR). Partial gastrectomy is reserved for those patients with severe hemorrhage.The initial differential diagnosis for acute fever without focal findings is extensive, including infectious, rheumatologic, and, less likely, oncologic disorders. Infectious causes considered in our patients were Epstein-Barr virus, CMV, and other viral infections, as well as occult bacteremia. However, when diagnostic test results for these infections came back negative, the differential diagnosis was expanded to include Bartonella, Brucella, Mycoplasma, Salmonella, and human herpesvirus 6 infections. Serologic tests for Bartonella henselae (cat scratch disease [CSD]) revealed an IgM titer of 1:160 and an IgG titer greater than 1:1,024. The results of a thorough evaluation for infectious and rheumatologic disorders were negative.CSD is a common disease in children mostly associated with self-limited regional lymphadenopathy but known to cause multiple clinical manifestations of varying severity. As reported by Florin et al, the true incidence of CSD is difficult to establish because it is not a reportable disease, and it is likely that many cases are not recognized because of self-resolution. In 2000, national CSD hospitalization rates ranged from 0.60 to 0.86 per 100,000 for children younger than 18 years, with an increased incidence in children younger than 5 years. Bartonella henselae, the causative organism, has broad distribution in North America and worldwide. The disease often follows a cat scratch or bite, which results in inoculation of the organism into the host. This aerobic gram-negative bacillus is transmitted by the cat flea, Ctenocephalides felis, between cats and transmitted to humans via cat saliva or the scratch of a cat. Cats, especially kittens younger than 1 year, are natural reservoirs for B henselae because the organism causes asymptomatic bacteremia that persists for a year or longer.The typical presentation of CSD (occurring in 85%-90% of children with Bartonella infection) is a cutaneous lesion appearing 7 to 12 days after a cat scratch or bite, followed days to weeks later by localized lymphadenopathy or lymphadenitis. A total of 10% to 30% of enlarged lymph nodes become suppurative. Regional lymphadenopathy is the hallmark of CSD; commonly, cervical and axillary lymph nodes are involved and can enlarge to several centimeters in diameter. Lymphadenopathy may persist for weeks to months, and patients with localized disease generally have a self-limited illness.Fever occurs in 30% to 50% of patients with CSD and can reach maximal temperatures of up to 104°F (40°C). However, in typical CSD, less than 10% of patients have high fever (temperatures >102.2°F [>39°C]), and one-third are actually afebrile. A total of 10% to 30% of CSD patients have prolonged fever as their only initial presenting symptom. In fact, CSD is the third most common infectious disease responsible for fever of unknown origin in children after Epstein-Barr virus infection and osteomyelitis. Fevers are less commonly associated with malaise, anorexia, rash, and other generalized symptoms.Manifestations of disseminated infection include visceral organ, neurologic, and ocular involvement. Visceral organ involvement of CSD generally includes hepatic and/or splenic lesions, one of the more common manifestations of CSD after isolated lymphadenopathy. However, many patients with visceral involvement have no accompanying peripheral adenopathy. CSD may cause multifocal necrotizing granulomas, leading to painful hepatosplenomegaly. Neurologic manifestations of CSD include encephalopathy (most common) and other less common manifestations, including transverse myelitis and cerebellar ataxia. Most patients with CSD encephalopathy recover within several weeks, but some patients have residual neurologic defects. Ocular manifestations of CSD include Parinaud oculoglandular syndrome or neuroretinitis. Parinaud oculoglandular syndrome has been reported in 2% to 8% of patients with CSD and includes conjunctivitis, conjunctival granuloma, and adjacent preauricular lymphadenopathy. Approximately 1% to 2% of patients with CSD develop neuroretinitis, presenting with acute visual loss from optic nerve edema, which generally resolves.Diagnosis of CSD is often suspected based on clinical findings; however, laboratory confirmation is required. It is suggested that 3 of 4 criteria be met to establish the diagnosis of typical CSD.In general, titers of B henselae IgG greater than 1:64 to 1:256 suggest acute infection, but retesting 10 to 14 days later is recommended, with titers greater than 1:256 strongly suggestive of active or recent infection. IgM is useful but known to increase only briefly in response to infection. PCR-based tests for B henselae are also available commercially.Culture of B henselae is not easily achieved because of the fastidious, slow-growing nature of the organism. However, B henselae can be visualized as pleomorphic bacilli in chains, clumps, or filaments on Warthin-Starry stain performed on lymph node and cutaneous lesion tissue specimens.The role of antimicrobial therapy in CSD is unclear. Most patients with typical CSD have gradual resolution of symptoms within 2 to 6 months, and antimicrobial therapy is not suggested for uncomplicated disease. Suppurative lymphadenopathy should be aspirated if they are painful; however, incision and drainage are not recommended because of potential chronic sinus tract formation. Most studies report no benefit to antibiotic therapy in CSD. Given the natural resolution of uncomplicated CSD and the risk of unnecessary antibiotic exposures, antibiotics are not suggested for typical CSD. In patients with extensive lymphadenopathy or who are immunocompromised or severely ill, especially patients with hepatosplenic disease, antibiotic therapy may be considered. The most commonly recommended therapy is azithromycin. Other antibiotics suggested include trimethoprim-sulfamethoxazole, gentamicin, ciprofloxacin, or rifampin. Our patient was treated with azithromycin and experienced rapid defervescence.The patient was placed on nasogastric tube feedings. The results of subsequent metabolic workup, including anion gap, free thyroxine, thyrotropin, sweat chloride test, stool elastase, α1-antitrypsin phenotype, carnitine and acylcarnitine profile, plasma amino acid, organic acid, and succinyl acetone from urine and serum, were normal. Hepatitis B, human immunodeficiency virus, CMV, Epstein-Barr virus, and human herpesvirus 6 antibody panel results were also negative. The results of electrocardiography and 2-dimensional echocardiography were normal. The underglycosylated transferrin level was slightly elevated but not enough to make a diagnosis of congenital disorder of glycosylation. Plain microscopy of skeletal and abdominal muscle revealed many ragged red fibers on trichrome stain consistent with the diagnosis of mitochondrial myopathy. On electron microscopy, liver and muscle tissue revealed irregular, swollen mitochondria with reduced cristae. The results of genetic studies for various mutations (eg, POLG, COX10, SCO2, SCO1, and SURF) were negative.Although the diagnosis of mitochondrial myopathies is primarily a clinical one, molecular and biochemical evaluations are required to confirm the specific diagnosis. All these disorders may follow mendelian inheritance (ie, nuclear DNA mutations) or maternal inheritance (ie, mitochondrial and mitochondrial DNA [mtDNA] mutations). Most pediatric mitochondrial diseases are caused by nuclear DNA mutations. Respiratory chain dysfunction (ie, problems with oxidative phosphorylation in the inner mitochondrial membrane) are conventionally termed mitochondrial myopathies.Clinical presentation of mitochondrial myopathies is extremely variable. Myopathies can present as an incidental finding or in association with multisystem illness. A detailed family history of childhood muscle or cardiac involvement, deafness, vision abnormality, diabetes, or developmental delay should be obtained. In neonates the most common presentation is an encephalomyopathic form of mitochondrial myopathy. In one study the median survival of those with infantile onset was 12 years. Defects in the respiratory chain invariably impair energy production in skeletal muscle. Potential defects can occur in complex 1, 2, 3, or 4 of the respiratory chain in mitochondria. Children with mitochondrial myopathies may have life-threatening complications during anesthesia due to underlying metabolic derangements.The most lethal form of encephalomyopathy of infancy and childhood presents at birth with severe hypotonia and may have associated brain, heart, kidney, or liver involvement. This presentation is generally secondary to mutation in the thymidine kinase 2 or succinyl COA synthase ligase 2 genes and is known as the mitochondrial depletion syndrome. Sometimes tubular dysfunction, such as Fanconi syndrome, is also associated with the mitochondrial depletion syndrome.Mitochondrial disorders can also present as various syndromes, such as Barth syndrome (cardiomyopathy, cyclic neutropenia, and mitochondrial myopathies), Leber hereditary optic neuropathy, Leigh syndrome (necrotizing encephalomyopathy), maternally inherited deafness and diabetes, myoclonic epilepsy and ragged red fibers, and Pearson syndrome (sideroblastic anemia and pancreatic insufficiency). Leigh syndrome and mitochondrial encephalopathy with lactic acidosis and strokelike episodes are the most common mitochondrial disorders.The diagnosis of mitochondrial disease can be made by family history, particularly in the case of maternal transmission. Sixty-two percent of cases result from nuclear DNA mutations and follow mendelian inheritance. The evaluation generally includes complete blood cell count, serum electrolyte measurement, fasting glucose measurement, glycosylated hemoglobin measurement, renal and liver function tests, creatine kinase measurement, plasma and cerebrospinal fluid lactate and pyruvate measurement, lactate to pyruvate ratio, plasma amino acid measurement, urine organic acid measurement, plasma acylcarnitine analysis, ammonia measurement, brain magnetic resonance imaging, thyroid studies, electromyography, nerve conduction studies, hearing studies, electroencephalography, and echocardiography. The ratio of lactate to pyruvate differentiates between pyruvate dehydrogenase deficiency and primary respiratory chain dysfunction. Because of defects in oxidative phosphorylation, patients with mtDNA disorders are dependent on anaerobic metabolism, which results in a shunt of pyruvate to lactate. Thus, as demonstrated in our patient, a high lactate level at rest and elevated lactate to pyruvate ratio is suggestive of an mtDNA disorder. Muscle biopsy is the gold standard test for diagnosing a mitochondrial disorder, and the classic hallmark is ragged red fibers on Gomori trichrome stain. Other stains that are used are succinate dehydrogenase and Cox stain. Overall, electron microscopy does not provide any additional helpful findings than plain microscopy but may reveal hypoplastic or dystrophic cristae.The management of mitochondrial disease is generally symptomatic and includes respiratory support and control of cardiac, ophthalmic, and neurocognitive problems. At this time there is no well-researched pharmacologic treatment, but various agents have been tried, including respiratory chain cofactors, antioxidants, agents that correct secondary biochemical deficits, and drugs that reduce lactic acid accumulation. The current research on gene therapy and approach of gene shifting is still in the investigational stages.To view Suggested Reading lists for these cases, visit http://pedsinreview.aappublications.org and click on the “Index of Suspicion” Link.