index of suspicion

Case 1 Presentation
A 2-month-old girl is admitted to the hospital because of a 2-day history of fever, lethargy, decreased appetite, and neck masses. She has had an intermittent but progressively worsening rash since birth, which was normal. She has had mild-to-moderate seborrheic dermatitis on her scalp and forehead. Three weeks ago, she was admitted for a rash and fever, which were treated as impetigo and cellulitis. On physical examination, the infant is irritable. Her temperature is 101F (38.4C), respiratory rate is 60 breaths/min, heart rate is 120 beats/min, and blood pressure is 90/60 mm Hg. Her skin shows scattered, hypopigmented, scaly ovoid lesions measuring 0.2 to 1 cm and multiple erythematous macular lesions with two necrotic areas from the head to the pelvis. Thick, greasy, crusted lesions are noted on her scalp. She has multiple 2- to 3-cm rm, nontender anterior and posterior cervical lymph nodes bilaterally. Her liver and spleen are enlarged and 4 cm and 6 cm below the coastal margins, respectively. Laboratory ndings include: Hgb, 4.8 g/dL (48 g/L); mean cell volume, 90 fL; mean cell hemoglobin, 26 pg; mean cell hemoglobin concentration, 29%; WBC count, (14.5109/L) 14.5103/mcL (36% neutrophils, 53% lymphocytes, 8% monocytes, 3% eosinophils); platelet count, 204103/mcL 9 (20410 /L); reticulocyte count, 10% (0.1); and C-reactive protein, 9.8 mg/L. Coagulation studies, serum electrolyte concentrations, and liver enzyme values are normal. A chest radiograph shows bilateral increased lung markings. Her bone marrow biopsy yields normal results. Bone survey reveals a single septal lucency in the right femur measuring 5 mm. Skin and lymph node biopsies

are performed, and the histologic ndings conrm the diagnosis.

Case 2 Presentation
A 5-month-old girl presents with a 1-week history of episodes described as sudden exion of the head, neck, and torso, with her upper limbs aring outward and inward, each lasting 1 to 5 seconds. She has 10 to 45 of these episodes in one cluster, with about three to four clusters per day. There are no alleviating factors or relationship to feeding, and no cyanosis or incontinence is noted. No other systemic signs are present. Family history reveals a seizure disorder diagnosed at 6 months of age in the mother, which was treated with adrenocorticotropic hormone (ACTH) for several years until she outgrew it. The father has bipolar disorder. On physical examination, all vital signs are within normal limits. The childs weight and length are at the 25th percentile, and her head circumference is at the 50th percentile. She rolls over, laughs, and is responsive. Physical ndings are otherwise normal, with no congenital nevi or dysmorphic features noted. A CBC, CSF analysis, amino acid prole, and urinalysis yield normal results. Blood, urine, and CSF cultures are negative; MRI and CT scan of the head appear normal. The interictal EEG tracing is severely abnormal, with a dysrhythmic background and evidence of generalized and multifocal spikes throughout the recording. No hypsarrhythmic pattern is noted. Resolution of seizures after treatment helps reveal the diagnosis.

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 rst by contacting Dr. Nazarian at LFredN@aol.com.

Author Disclosure Drs Eneli, West, Sigal, Lazerson, Halthore, LaBeaud, Leonard, and McComsey and Mr Martel did not disclose any nancial relationships relevant to these cases.

Frequently Used Abbreviations

alanine aminotransferase aspartate aminotransferase blood urea nitrogen complete blood count central nervous system cerebrospinal uid computed tomography electrocardiography emergency department electroencephalography erythrocyte sedimentation rate GI: gastrointestinal GU: genitourinary Hct: hematocrit Hgb: hemoglobin MRI: magnetic resonance imaging WBC: white blood cell ALT: AST: BUN: CBC: CNS: CSF: CT: ECG: ED: EEG: ESR:

Case 3 Presentation
An 18-month-old girl has been ill for 3 weeks with worsening cough and difculty breathing. There has been no fever, weight loss, night sweats, or
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index of suspicion

decreased activity. Two weeks ago, she was diagnosed as having a viral upper respiratory tract infection and given albuterol for dyspnea. Since then, her symptoms have progressed. She has had no signicant past illnesses, is fully immunized, and is taking only albuterol. Both parents are healthy. The patient has not traveled. On admission, the girl is in mild respiratory distress, with a respiratory rate of 40 breaths/min, a temperature of 100.6F (38.1C), a heart rate of 110 beats/min, and a pulse oximetry reading of 93% on 1 L of oxygen. Her weight and length are below the 5th percentile. Her tonsils are 3 enlarged and mildly erythematous. Tiny cervical and inguinal lymph nodes are palpable. She has mildly decreased breath sounds on the left without crackles, rhonchi, or wheezes and shows no retractions, grunting, or aring. All other physical ndings are normal. A chest radiograph appears normal. Her WBC count is 11.1103/ mcL (11.1109/L) (76% neutrophils, 22% lymphocytes), Hgb is 10.8 g/dL (108 g/L), and platelet count is 281103/mcL (281109/ L). Electrolyte and liver transaminase levels are normal. A puried protein derivative (PPD) tuberculin test result measures 1415 mm. Bronchoscopy reveals a large, obstructive, polypoid lesion in the left mainstem bronchus. Broncheoalveolar lavage uid shows 3 granulocytes with negative fungal, acid-fast bacillus, and Gram stains. Biopsies are sent for cultures and histologic examination, which shows acute and chronic inammation.

The Condition
The childhood histiocytoses comprise a diverse group of disorders characterized by the accumulation of histiocytes, which are mononuclear phagocytic cells, in different organ systems. Histiocytes originate from the bone marrow, undergoing multiple maturational steps into a monocyte, which is found in the peripheral blood. Additional terminal differentiations in the monocytes occur in different tissues in the body. For example, they are known as Kupffer cells in the liver and Langerhans cells in the skin. Normally, the Langerhans cell is the most efcient presenter of antigen. However, in LCH, the cell has lost this ability. It is believed that immunologic stimulation of the Langerhans cells results in uncontrolled proliferation and accumulation, destroying tissue. This pathophysiologic process is worsened through cytokine production by the abnormal cells. Childhood histiocytosis can be classied in terms of histologic ndings, determined by the type of histiocyte involved in the disease. The dendritic cell-related histiocytoses include LCH and juvenile xanthogranuloma. LCH, previously known as histiocytosis X, is comprised of the clinical entities known historically as eosinophilic granuloma (solitary lytic lesion of bone), Hand-Schu ller-Christian disease (classic triad of lytic skull lesions, diabetes insipidus, and exophthalmos), and Letterer-Siwe disease (systemic disease with involvement of the lung, liver, and bone marrow and a purpuric rash). The second histologic grouping includes disorders of antigenphagocytosing macrophages: familial erythrophagocytic lymphohistiocytosis, infection- or malignancy-associated hemophagocytic syndrome, and Rosai-Dorfman disease. The staging classication for

LCH is divided into two primary groups: single- and multisystem disease. In single-system disease, the skeletal system is involved most frequently (single or multiple site), followed by skin and lymph nodes. The multisystem disease is differentiated further based on the presence or absence of organ dysfunction of the liver, lung, spleen, or hematopoietic system. This patient, who had bone, skin, lymph node, liver, and spleen involvement as well as anemia (denoting organ dysfunction), presented with the subgroup seen in approximately 15% of LCH cases. This staging classication is used most often in clinical practice and also guides treatment. The annual prevalence of the childhood histiocytoses is estimated to be 4 per 1 million children. However, this gure may be an underestimate because of the diverse clinical presentations and diagnostic difculty associated with the histiocytosis syndromes. The male-to-female ratio is 1.3:1, with variable peak incidence, depending on the disorder type.

Clinical Presentation
In LCH, which is the most common form of histiocytosis, the presentation varies. Lytic bone lesions, which can involve the skull, vertebral bodies, ribs, scapula, and femur, occur in approximately 80% of patients. Most of these bone lesions are asymptomatic or can present as raised, soft, tender areas. Lesions in the periorbital region may cause proptosis. Skin involvement can be generalized or localized, manifesting as seborrheic dermatitis of the scalp, purpuric or necrotic lesions, or diffuse candidal diaper dermatitis. Patients also can have gingival hypertrophy; ulcers of the palate, buccal mucosa, tongue, or lips; chronic otitis externa; and pancytopenia. Localized or dissemi-

Case 1 Discussion
Findings on biopsy conrmed that this infant had multisystem Langerhans cell histiocytosis (LCH) with organ dysfunction.
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nated lymphadenopathy is seen in 33% of patients. Approximately 20% of patients have hepatosplenomegaly, with increased liver enzyme values, hypoalbuminemia, hyperbilirubinemia, clotting factor deciencies, and hypersplenism. Pulmonary inltrates, diffuse brosis, and disseminated nodular inltrates can be seen on imaging studies. Encroachment on the pituitary gland, especially the posterior fossa (reported in 5% to 50% of patients) causes endocrine abnormalities, such as growth retardation and diabetes insipidus. CNS ndings due to inltration by the proliferating Langerhans cells or pressure on surrounding structures include seizures, nystagmus, paresis, ataxia, and headache.

Making the Diagnosis

The diagnosis is based on the histologic ndings of a skin, lymph node, or bone biopsy. The presence of CD1a surface marker and characteristic, racquet-shaped bodies in the cytoplasm in the lesional cells that are visible on electron microscopy (Birbeck granules) establishes the diagnosis. Other diagnostic investigations are dictated by the clinical presentation and can include a skeletal survey to assess bone involvement, chest radiograph to detect pulmonary involvement, and urine and serum osmolality measurements when diabetes insipidus is suspected.

lesion. For example, painful osseous lesions can be curetted and systemic steroids can be given for localized skin involvement. In treating multisystem disease, different chemotherapeutic agents are used, alone or in combination. Experimental therapies suggested for unresponsive disease include immunosuppressive therapy with cyclosporin/antithymocyte globulin, radiation, or bone marrow transplantation. Long-term follow-up for all patients is indicated because the clinical course is variable and sequelae fairly common, including diabetes insipidus, growth retardation, pulmonary brosis, developmental delay, ataxia, dysarthria, and malignancies such as leukemia. This patient received a 1-year course of chemotherapy with vinblastine, methotrexate, 6-mercaptopurine, and prednisone, and she responded very well. At her most recent visit, at 212 years of age, all investigative studies, including CT scans of her neck, abdomen, and pelvis, yielded normal results. Her growth and development have been appropriate for age.

mal EEG that did not demonstrate a hypsarrhythmic pattern. Initially the infant was given topiramate and phenobarbital, but despite the attainment of therapeutic serum levels, the seizures continued. Seizure activity ceased after the child was treated with ACTH. The clinical picture, together with her response to ACTH in the setting of failed traditional anticonvulsant therapy, makes a very strong case for the diagnosis of cryptogenic IS despite the absence of a hypsarrhythmic pattern on EEG.

The Disorder
IS is a unique disorder of infancy and early childhood and typically is classied into two groups: cryptogenic and symptomatic, with approximately 10% to 20% of cases being of the cryptogenic type. Infants who have cryptogenic IS are those whose mothers experienced unremarkable pregnancies. The infants experienced unremarkable births, developed normally until the onset of the spasms, and have normal ndings on neurologic examination and radiologic studies. Patients who have symptomatic IS manifest impaired development even before the spasms appear and have several prenatal, perinatal, and postnatal factors in association with the seizure disorder. IS typically arises at 3 to 6 months of age. The episodes are characterized by seizures consisting of brief, symmetric contractions of the neck, trunk, and extremities that typically last 1 to 5 seconds. In the typical seizure, the patient suddenly jerks, nods, or slowly bends forward. These seizures often occur in clusters of a dozen to hundreds of episodes and frequently are seen soon after arousal from sleep. Infants possessing the triad of infantile spasms, hypsarrhythmia, and mental retardation are said to have West syndrome.
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Lessons for the Clinician

Although the histiocytoses are relatively rare, pediatricians should be aware of them because they can mimic common disorders. Skin lesions can be mistaken for severe seborrheic dermatitis or a petechial rash can suggest meningococcal infection, especially if the child is febrile and has systemic involvement. Early diagnosis can minimize morbidity and improve the prognosis. (Ihuoma Eneli, MD, MS, Markeeta West, MD, Yakov Sigal, MD, Michigan State University, East Lansing, Mich.)

Treatment and Prognosis

The class of histiocytosis and clinical presentation determine treatment, the primary goal of which is to reduce complications and morbidity. When the disorder is limited to one organ system, the clinical course generally is benign. Treatment can consist simply of observation or minimal intervention can be taken that is directed at arresting the progression of the

Case 2 Discussion
This child had cryptogenic infantile spasms (IS) associated with an abnor-

index of suspicion

Diagnosis
The diagnosis of IS often is delayed because the unique motor phenomena may be mistaken for startle responses, Moro reexes, colic, hypnagogic jerks during sleep, or other myoclonic activity. Additionally, IS can be confused with benign myoclonus of infancy, which may be characterized by repetitive jerks. The seizures of benign myoclonus of infancy, however, typically are briefer and respond to conventional anticonvulsants, and 3-Hz spike-andwave or polyspike-and-wave activity is exhibited on EEG during the seizure. Conversely, the EEG pattern most commonly associated with IS is referred to as hypsarrhythmia, consisting of random, high-voltage, bilaterally asynchronous slow-wave activity in the setting of a disorganized background, multifocal spikes, and burst-suppression, wherein an upsurge of brain activity is followed by diminishing activity. Although the EEG often shows this hypsarrhythmic pattern, IS ultimately is a clinical diagnosis.

symptomatic IS, positive correlations have been made with several prenatal and perinatal risk factors, including cerebral palsy, prematurity, hypoxicischemic encephalopathy with periventricular leukomalacia, congenital and CNS infections, inborn errors of metabolism, tuberous sclerosis, cytoarchitectural abnormalities (lissencephaly, schizencephaly), and head trauma (subdural hematoma, intraventricular hemorrhage).

cognition still is affected by the disorder, and most children suffer signicant developmental disability. Although more than 50% of children who have IS develop other seizure disorders, the characteristic spasms typically resolve by mid-childhood regardless of treatment.

Lessons for the Clinician

Epileptic spasms in clusters beginning in the rst postnatal year without a hypsarrhythmic EEG pattern may represent a subtype of IS that may be refractory to antiepileptic drugs. If an infant presents with classic seizures characterized by frequent episodes of rapid exing of the arms and legs and a family history of neurologic disorders, including IS, but without denite hypsarrhythmia, the clinician still should consider treatment with ACTH. (1) (Joseph N. Martel, MS-IV, Jack Lazerson, MD, Srivinas N. Halthore, MD, University of Nevada School of Medicine, Las Vegas, Nev.)

Prognosis and Management

Although the clinical outcomes of patients who have true cryptogenic IS are better than those aficted with symptomatic IS, most infants have a poor outcome, exhibiting mental retardation, chronic epilepsy, and other neurodevelopmental abnormalities. The underlying cause of any patients IS is the most important prognostic factor in long-term developmental outcome and neurologic functioning. Better clinical outcomes have been associated with normal neurologic examination ndings at the onset of the disorder, achievement of expected developmental milestones, older age at onset, absence of other seizure types, short duration of spasms, and early effective treatment of spasms. Although specic therapy remains highly controversial, treatment of IS with exogenous ACTH or prednisone, which is believed to inhibit hypothalamic CRH production and perhaps suppress neuronal hyperexciteability, offers effective seizure control for approximately 70% of patients. As with ACTH, the efcacy of anticonvulsants depends on EEG ndings and comorbidities. There is no consensus to date on optimal treatment or predictive factors for good responsiveness to ACTH. Clinicians should realize that ACTH treatment may improve the seizure problem, but the development of

Reference
1. Oguni H, Funatsuka M, Sasaki K, et al.
Effect of ACTH therapy for epileptic spasms without hypsarrhythmia. Epilepsia. 2005; 46:709 715

Causes
The cause of infantile spasms is unknown, although several leading hypotheses involve dysfunction of brainstem monoaminergic neurotransmitters, derangement of neuronal brainstem structures, and immune system abnormalities. One hypothesis implicates the hypothalamus-pituitaryadrenal axis, wherein corticotrophinreleasing hormone (CRH) stimulates the pituitary to release ACTH. By feedback inhibition, ACTH and glucocorticoids suppress the production and secretion of CRH. It is suggested that CRH excess, whether genetically based or resulting from stresses or injury during a critical period of neurodevelopment, produces neuronal hyperexciteability and seizures. Additionally, for infants who have
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Case 3 Discussion
With the history of an endobronchial lesion and a positive PPD result, the patient initially was believed to have Mycobacterium tuberculosis (MTB) infection; was placed in a negative pressure room; and was given isoniazid, rifampin, streptomycin, and pyrazinamide. All family members underwent tuberculin skin testing, but none had reactive tests. After complete resolution of her symptoms, the patient was discharged on isoniazid, rifampin, streptomycin, and pyrazinamide, with appropriate follow-up and a probable diagnosis of medias-

index of suspicion

tinal mass caused by tuberculosis (TB). Her acid-fast bacillus culture ultimately grew Mycobacterium avium complex (MAC) that was susceptible to clarithromycin, ethambutol, rifabutin, and rifampin, at which time her therapy was changed to clarithromycin and rifabutin. Follow-up examinations and CT scan of the chest showed the endobronchial lesion responding to therapy and normalization of her ndings. Three months after the initial hospitalization and 6 weeks after starting MAC therapy (missing no doses), progressive breathing difculty for 4 days led her to rehospitalization. She was in moderate respiratory distress and demonstrated increased cervical and inguinal lymphadenopathy and markedly decreased breath sounds on the left. Repeat CT scan showed an overall decrease in the size of her mediastinal mass, but bronchoscopy again found near-complete occlusion of her left mainstem bronchus and 20% occlusion of the right. Massive debulking led to marked improvement.

caused by NTM usually is limited to patients who have predisposing pulmonary disease, notably cystic brosis. Cutaneous NTM infections are rare in children, but can follow percutaneous inoculation by water contaminated with M marinum and can progress to a swimmers granuloma. M abscessus has been implicated in outbreaks of otitis media associated with ear tube placement and contact with contaminated water or equipment. The rapidly growing mycobacteria, M fortuitum, M chelonae, and M abscessus, have been implicated in soft-tissue, bone, and central catheter infections. Disseminated NTM infections usually are caused by MAC and are limited to people who have impaired cell-mediated immunity.

Diagnosis
Diagnosis of NTM disease usually is based on histologic ndings, which show noncaseating granulomas, with or without acid-fast bacilli. Denitive diagnosis of NTM requires isolation of the causative organism. Many of the NTM infections require special nutrition and incubation practices. Therefore, when NTM is in the differential diagnosis, it is prudent to inform the laboratory. Isolation of the infecting strain and additional susceptibility testing facilitates ideal therapy because NTM species have varied antibiotic susceptibilities. A total of 2 to 4 weeks generally are required for NTM to grow in culture and another 4 to 6 weeks for speciation and susceptibility testing. M fortuitum, M chelonae, and M abscessus commonly are referred to as the rapidly growing mycobacteria because they grow sufciently for identication in as few as 3 to 7 days.

The Agents
Many species of nontuberculous mycobacteria (NTM) have been identied, but only a few are considered pathogens in children. MAC, M fortuitum, M kansasii, and M marinum are the most common agents causing childhood NTM infections. Several syndromes can be caused by NTM, the most common being cervical lymphadenitis, of which 80% of cases are caused by MAC. In the United States and other developed countries, lymphadenitis caused by NTM is more common than that caused by MTB. Less common NTM infections include cutaneous infection, otitis media, central catheter infection, osteomyelitis, and pulmonary infection, as in this case. Pulmonary disease

The Specic Agent

MAC, like many other species of NTM, is ubiquitous. It is a common environmental isolate, found in fresh

water and saltwater around the world, and rarely becomes a pathogen in an immunocompetent host. The clinical manifestations of MAC disease in children can range from a localized cutaneous granuloma to disseminated disease. Infections with MAC in children who have normal immune function usually are limited to unilateral, nontender, subacute, cervical, submaxillary, or submandibular lymphadenitis and resolve after surgical excision. Affected children generally remain well, with no constitutional symptomatology, and often have a modestly reactive (12 mm) PPD skin test result. Disseminated MAC infections are limited to patients who have severely altered immune function, such as in advanced human immunodeciency virus (HIV) infection. Patients present with systemic signs of fever, weight loss, night sweats, fatigue, abdominal pain, diarrhea, lymphadenopathy, hepatosplenomegaly, and anemia and often have no prior history of immunodeciency. They warrant a thorough immune evaluation. Although pulmonary manifestations of NTM are common in adult patients, it is rare for an immunocompetent child to develop a severe NTM infection, especially one that has such prominent pulmonary ndings as reported for the child in this case. Children who have pulmonary NTM disease tend to present with inltrates, fever, and cough, as well as localized wheezing from compression of the airways by enlarged hilar nodes, and usually are infected with MAC. The child in this case had no predisposing pulmonary disease, developed cough, and was found to have an obstructive endobronchial mass due to MAC. In immunocompetent children, MAC can cause endobronchial lesions that may be misdiagnosed as TB, as occurred in this patient. Thus, MAC should remain
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in the differential diagnosis until cultures conrm the organism. The differential diagnosis for this child included TB, endemic fungal infections, Bartonella infection, and neoplasm. Because of her extensive symptomatology and progression despite appropriate therapy, her immune system was evaluated thoroughly and repeatedly for evidence of cellular dysfunction. All tests, including HIV, T-cell subsets and mitogen studies, and genetic evaluation for impaired interferon-gamma-mediated immunity, were unrevealing.

Therapy
As is often the case with cervical lymphadenitis caused by MAC, the clinical course of endobronchial MAC disease is unpredictable. Although spontaneous resolution can occur, recurrences or reactivation within the rst year of onset are common. Despite excision, which may not always be achievable, medical options such as therapy with both clarithromycin and rifabutin remain the

mainstay of MAC therapy. It is important to note that although most children respond to these medications, progression may occur, and reexcision may become necessary. This case demonstrates that despite adequate NTM coverage and normal immune function, disease may progress and require multiple surgical interventions. Although this patient was receiving the classic, accepted regimen of clarithromycin and rifabutin, her disease progressed. In this case, the progression of her lesion came to medical attention quickly because of its location in her mainstem bronchus; other cases may be more insidious. It remains important to monitor meticulously for disease progression, despite excision and appropriate therapy. The need for or effectiveness of antimicrobial therapy for pulmonary NTM has not been established. No authoritative guidelines exist for the treatment of children who have these infections, and a variety of treatments are used across the

United States. The signicance of in vitro susceptibilities for NTM pathogens remains unclear and, therefore, should not be used solely to dictate choice of antimycobacterial drugs. Optimal duration of therapy also is uncertain. In this case, clarithromycin and rifabutin were continued for 9 months after her nal excision, and the patient did well. At her most recent follow-up visit, she was healthy 6 months after stopping all therapy.

Lessons for the Clinician

Mycobacterial infections, both tuberculous and nontuberculous, must be kept in mind when children present with lymphadenopathy or pulmonary disease. Although not common, severe NTM disease can occur in immunocompetent children. (A. Desiree LaBeaud, MD, Ethan G. Leonard, MD, Grace A. McComsey, MD, Rainbow Babies and Childrens Hospital, Cleveland, Ohio)

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