Index of Suspicion

[Alon]

Постараюсь публиковать здесь интересные клинические случаи по детским болезням.
К участию и обсуждению приглашаются все желающие.
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Case 1
Presentation

A 21-month-old boy known to have chronic gastroesophageal reflux is brought to your office for a second opinion regarding poor growth. Born at term, he was diagnosed as having reflux at 3 weeks of age due to arching and crying with feedings. He was noticed to be failing to thrive initially at 12 months of age when, despite adequate caloric intake, his weight percentile had fallen from the 75th to the 5th percentile over 6 months. His height and head circumference have remained between the 10th and 25th percentiles. He has experienced intermittent episodes of constipation and frequent colds and ear infections. He walked at 15 months of age and says about 150 words.

His evaluation has included multiple laboratory tests, including cystic fibrosis and celiac disease screening, thyroid function tests, CBC, measurement of electrolytes, and urinalysis. He has been evaluated by pediatric gastroenterology, and despite a formula change and multiple antireflux medications, his weight has remained in the 5th percentile. A pH probe study and endoscopy performed at 20 months of age demonstrated only mild reflux. He has had negative skin testing for food allergies.

The diagnosis is revealed after additional history and a laboratory test are obtained.
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Case 1 Discussion

On further questioning, the child’s mother mentioned that he drinks about 70 to 80 oz of fluid a day! Generally, he drinks 40 oz of water, 16 oz of rice milk, and two to three cans of liquid dietary supplement. This excessive thirst started at about 6 months of age. He awakens three to five times a night asking for water, and his wet diapers are noted to be incredibly heavy.

Measurement of urine electrolytes demonstrated concentrations of sodium below 5 mEq/L (5 mmol/L) and chloride below 20 mEq/L (20 mmol/L), with urine osmolality below 50 mOsm/L while the serum osmolality was high-normal at 303 mOsm/L. In retrospect, previous urinalysis results had been abnormal because of a specific gravity of 1.005, although the other indices had been normal. His serum chloride value had been mildly elevated at 109 mEq/L (109 mmol/L), but his sodium value was normal at 144 mEq/L (144 mmol/L).

The boy was admitted to the hospital for a water deprivation test, which showed an increase of serum sodium (from 144 to 152 mEq/L [144 to 152 mmol/L]), increase in serum osmolality (from 297 to 310 mOsm/L), no change in urine osmolality (range, 64 to 77 mOsm/L), and continued passage of dilute urine (specific gravity below 1.003). His weight decreased 5% (9.4 kg to 8.95 kg), and his urine volume averaged 16 mL/kg per hour.

After an injection of arginine vasopressin (AVP), his urine osmolality and specific gravity remained low at 70 mOsm/L and 1.002, respectively. His urine output was more than 30 mL/kg per hour during the subsequent hour after injection. The diagnosis of congenital nephrogenic diabetes insipidus (CNDI) was confirmed.

The Signs
Causes of polyuria and polydipsia can be differentiated based on laboratory values. Solute diuresis can be identified by finding a urine-to-plasma osmolality ratio greater than 0.7. Examples of solute diuresis are diabetes mellitus and intrinsic renal disease, which can be determined by routine chemistries. Water diuresis, in addition to a urine-to-plasma osmolality of less than 0.7, demonstrates a urine specific gravity below 1.010. Three common causes of water diuresis are compulsive water drinking, central diabetes insipidus (CDI), and nephrogenic diabetes insipidus (NDI).

Compulsive water drinking can be differentiated from diabetes insipidus (DI) by laboratory testing, if the history is not forthcoming. Interestingly, compulsive water drinkers often have a preference for ice water and are less likely to have nocturia. Low serum osmolality combined with low urine osmolality suggests compulsive water drinking.

CDI often can be suspected on the basis of history, as when the patient manifests brain tumor, head trauma, or CNS infection. In approximately 25% of cases, no cause can be determined.

It is important to differentiate congenital from acquired causes of NDI, such as drug effects, electrolyte disorders, urinary tract obstruction, and systemic disorders such as sickle cell anemia. It is helpful to recall that acquired NDI can be caused by primary renal disease, systemic disease with renal involvement, medication effects, and miscellaneous conditions.

Making the Diagnosis
If the patient can drink freely, the baseline serum sodium concentration generally normalizes, and there is no evidence of dehydration. A first step to distinguish NDI from other causes of polydipsia is to collect a 24-hour urine sample. For a small child, a shorter collection period may be necessary. The finding of polyuria in a patient who is dehydrated and has an elevated serum sodium concentration as well as hypo-osmolar urine implies a renal concentration defect. The diagnosis of NDI is confirmed by a water deprivation test, with results showing the inability to concentrate the urine despite the release of vasopressin.

The water deprivation test involves dehydrating the patient and testing for changes in specific laboratory values. Generally, the criteria for dehydration are 3% to 5% weight loss, orthostasis, a plateau in urine osmolality, or hypernatremia. Urine volume, osmolality of plasma and urine, and electrolyte values are followed closely. A plasma vasopressin level is measured at the start and completion of dehydration.

Both types of DI are characterized by the inability to concentrate urine after water deprivation. The urine osmolality usually remains below 200 mOsm/kg H2O, and the urine specific gravity remains below 1.010. On the other hand, compulsive water drinkers pass concentrated urine (urine osmolality >500 mOsm/kg H2O) after being deprived of water. Patients who have CDI demonstrate inadequate concentrations of vasopressin after a water deprivation test, but concentrations are elevated in those having NDI. To distinguish CDI further from NDI, vasopressin is administered. Individuals who have CDI have a significant increase (usually >50%) in urine osmolality after vasopressin is administered either intranasally, subcutaneously, or intravenously. Patients having NDI maintain a low urinary osmolality (usually <200 mOsm/kg).

The Condition
CNDI is a genetically inherited error, with 90% of cases being X-linked and 10% involving an autosomal recessive or autosomal dominant mechanism. The distal nephron is insensitive to the antidiuretic effects of AVP, which leads to the production of large amounts of hypotonic urine. Normally, in the collecting duct, AVP from the posterior pituitary gland binds with the vasopressin type-2 receptor (V2R), which activates adenylate cyclase to increase cyclic AMP. This reaction stimulates protein kinase A, which redistributes aquaporin-2 water channels (AQP2), permitting the apical plasma membrane to become permeable to water. As a result, water flows from the tubular lumen to the medullary interstitium, which produces concentrated urine. In the X-linked form, the mutation exists in the V2R gene; in the autosomally inherited forms, the mutation is in the AQP2 gene.

Clinical Features
Classic features of DI are polyuria and polydipsia, which can lead to hypernatremic dehydration. The excessive fluid intake also may blunt the appetite. Nonspecific signs and symptoms include failure to thrive, recurrent fevers due to dehydration, vomiting or poor feeding, and constipation. More severe manifestations are seizures and mental retardation, which occurs rarely because awareness of the disorder has increased. Physical findings may be normal or the patient may show signs of dehydration and irritability.

Treatment
CNDI is treated by dietary restrictions and medication. Sodium intake is reduced to 0.7 mEq/kg per day, and protein intake is decreased to 8% of total caloric intake to decrease renal solute load and decrease the volume of urine required for solute excretion. Thiazide diuretics, often coupled with potassium supplements, or potassium-sparing diuretics with dietary changes paradoxically can reduce urine volume by 20% to 50%. Amiloride and prostaglandin synthetase inhibitors have been used in combination with thiazide diuretics. Nonsteroidal anti-inflammatory drugs are useful in the acute setting to reverse hyperosmolality. It is important to remember that an increase in urine osmolality to more than 200 mOsm/kg H2O has a dramatic effect on urinary losses.

Lessons for the Clinician
A comprehensive history is essential in determining a cause for failure to thrive. Growth failure can be a presenting sign of CNDI. It is important to ask not only about inadequate urination and oral intake, but also about polyuria and polydipsia.


Laurie Liang, MD
Kaiser Santa Clara Hospital, Santa Clara, Calif

[Alon]

Case2
Presentation

A 3-year-old boy is seen in the ED because of a "bloodshot eye." Several weeks ago he was hit in the eye with a ball. Two days ago his eye became red but has not bothered him. He has had no ocular discharge, fever, or respiratory symptoms. He comes from a disrupted family complicated by parental drug use and has siblings in foster care. He has not received routine care, although he was seen regularly in infancy and is fully immunized.

Physical examination reveals an active, well-nourished toddler who has conjunctival injection and a blood layer in the anterior chamber of his right eye (hyphema). There appears to be no vision in his affected eye, and a red reflex cannot be obtained. There are no signs of facial trauma, strabismus, or pigmented yellow lesions around the eye. Examination of the skin shows no petechiae or bruising except on the anterior shins. The child is admitted for management of hyphema.

Laboratory findings include a WBC count of 8.5x103/mcL (8.5x109/L), Hgb concentration of 12 g/dL (120 g/L), platelet count of 275x103/mcL (275x109/L), international normalized ratio of 1, and partial thromboplastin time of 41 seconds. A skeletal survey shows no fractures. Imaging confirms the cause of the hyphema.
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Case 2 Discussion

Further history revealed that the child’s right eye has glowed like a "cat’s eye" when viewed from across the room since he was 24 months old. CT scan revealed a calcified mass within the right globe and no abnormalities of the left globe. The findings of a calcified mass within the globe on CT scan were consistent with retinoblastoma.

The Condition
Hyphema in children most commonly occurs after blunt or lacerating trauma, but the differential diagnosis is broad. Spontaneous hyphema can arise from juvenile xanthogranuloma, leukemia, hemophilia, thrombocytopenia, aspirin or warfarin ingestion, and intraocular tumors such as retinoblastoma.

Although hyphema in children usually resolves without sequelae, complications can ensue and include increased intraocular pressure, optic atrophy, synechiae between the iris and the lens, and corneal blood staining. Because complications are more common with rebleeding, initial management is aimed at preventing further bleeding. Placement of a hard metal shield to protect the eye (Fox shield) is an important preventive step. Bed rest or quiet ambulation should be instituted, along with elevation of the head of the bed. Admission should be strongly considered for all children, especially if there is any question of compliance. Because patients who have sickle cell hemoglobinopathy are at higher risk for complications, Hgb electrophoresis should be obtained if the diagnosis is in question.

Ophthalmologic consultation is required for any child presenting with hyphema to prevent late sequelae. The ophthalmologist administers medicines that lower intraocular pressure, decrease inflammation, and prevent synechiae. Surgical intervention is considered if intraocular pressure cannot be managed with maximal medical therapy or if corneal blood staining occurs.

The Underlying Condition
Retinoblastoma, although rare, is the most common malignant intraocular tumor in children (incidence of 1 in 17,000) and must be considered in any case of spontaneous hyphema. The tumor typically is diagnosed in the first years after birth. The initial sign usually is leukocoria, and family members often describe a glow or cat’s eye appearance. Retinoblastoma also can present with strabismus, hyphema, and periocular inflammation resembling orbital cellulitis. The disease can be familial or sporadic and can present unilaterally or bilaterally. Bilateral disease almost always is familial. A mutation of the retinoblastoma gene (a tumor suppressor gene) on chromosome 13 is responsible for tumor development. Metastasis is uncommon. Spread can occur by direct extension along the optic nerve into the brain or the subarachnoid space or through the bloodstream to bone, bone marrow, lung, and lymph nodes. When retinoblastoma is diagnosed, both parents and all siblings should be examined for retinoblastoma.

The management of retinoblastoma involves a multidisciplinary team using multiple modalities that prioritize tumor eradication. Careful and judicious attempts should be made to preserve vision. Treatments include chemotherapy, external beam radiation, laser photocoagulation, enucleation, or combinations of these approaches. Although enucleation remains the most common treatment for unilateral disease, the trend in more recent years has been toward less frequent use of this approach, probably because of the more effective use of other approaches such as radiation, chemotherapy, and laser therapy. The prognosis for patients who have unilateral retinoblastoma without optic nerve invasion or metastasis is excellent, with more than 90% survival among those using current therapy. However, if tumor is disseminated, the mortality increases substantially. Surgical washout, which sometimes is performed for bleeding in the eye, carries the potential for dissemination, which could have proved a lethal choice for this child.

Lessons for the Clinician
The possibility of retinoblastoma should be entertained for any child who develops a spontaneous hyphema. In this case, the child’s complicated social situation might have led the clinician to suspect nonaccidental trauma as the cause of the child’s hyphema, delaying the diagnosis. When the retina cannot be visualized, it is imperative to obtain an imaging study to rule out disease in the posterior pole.


Carrie Phillipi, MD, PhD
Laurie Christensen, MD
John Samples, MD
Oregon Health and Science University, Portland, Or

[Alon]

The knotty problem in an infant girl's groin
Jul 1, 2005
By: Doran L. Fink, MD, PhD, Janet R. Serwint, MD

Mid-afternoon, and you're working at the pediatric clinic of your university hospital. With the beautiful spring weather outside, you've seen few acute care visits today; itchy eyes and runny noses in otherwise healthy children have established an unusually relaxing pace! Only one patient remains to be seen: a nearly 3-month-old girl whose mother is concerned about a "knot in the baby's groin."

Mom greets you with an uneasy smile as you enter the examination room. "It hasn't gone away," she says. "I think it's gotten bigger."

Instantly, you remember that the last time you saw the infant was four weeks ago—at her 2-month-old health maintenance visit. She had a diaper rash.

Reviewing your notes from that encounter, you recall that the rash had appeared one week before that visit. Apart from that, your patient was growing well, without complaints of fever, cough, congestion, diarrhea, or emesis. She was afebrile; vital signs were normal for age. You noted a pink, macular, anterior inguinal rash with satellite lesions that suggested diaper candidiasis. You also noted a firm, nontender, 1 x 1-cm mass in the right inguinal area that was freely mobile. Otherwise, the exam was unremarkable with no other rash or palpable mass.

Having decided that the inguinal rash was most consistent with a candidal infection and the mass most consistent with a reactive lymph node, you prescribed nystatin cream to be applied until three days after the rash resolved. You instructed the mother to return to the clinic if either the rash or the lymph node persisted for longer than several weeks. Now, four weeks later, she informs you that the rash did indeed improve within a week after the nystatin was started. The mass in the right groin has not disappeared as expected, however; instead, she reports that its size has nearly doubled!

The patient takes her lumps On further questioning, you learn that the mass has been present continuously over the past four weeks. It has remained nontender and does not appear to bother the baby when it is touched or when it is manipulated during a diaper change. The patient has regular, soft, yellow-to-brown bowel movements several times a day; no blood is obvious in the stool. She has had no emesis and has been taking formula well—four ounces every four or five hours. She has still not had a fever.

Today, rectal temperature is 36.4° C; heart rate, 150/min; and respirations, 42/min. Weight is 3.91 kg (between 5th and 10th percentiles for postconceptual age, tracking along her expected growth velocity). Overall, she is alert and active and appears well. The anterior fontanelle is soft; sclerae are clear; and a pupillary red reflex is present bilaterally. Tympanic membranes are unremarkable. Oropharynx is moist with no enanthem. Neck is supple without lymphadenopathy. Examination of the heart and lungs is unremarkable. The abdomen is soft and nontender, with normal bowel sounds and no organomegaly.

When you remove the girl's diaper, you discern the firm, freely mobile subcutaneous mass in the right inguinal region, midline along the path of the inguinal canal. The mass is 2 x 1.5 cm, nontender on palpation and manipulation, nonpulsatile, and lacking overlying skin changes. Turning to the left inguinal region, you palpate two firm, mobile, nontender masses, each 0.5 x 0.5 cm. You find no other palpable masses. Surveying the baby's skin carefully, you find no rashes anywhere. There are several small areas of hypopigmentation along the inguinal creases and inner thighs.

You're intrigued by the persistence of these inguinal masses. As a first step, the mother—20 years old, with negative serologic tests for syphilis, hepatitis B, and HIV infection—recounts her daughter's medical history for you.

The patient was born prematurely, at 35 weeks' gestation, product of an identical twin pregnancy. Vaginal delivery was complicated by breech presentation; the baby required positive pressure ventilation for several minutes for respiratory distress. Apgar score was 3 at one minute, 7 at five minutes, and 8 at 10 minutes. She was admitted to the neonatal intensive care unit, where she remained stable on room air. A workup for sepsis was negative. After two days in the NICU, she was transferred to the well-baby nursery. Three days later, she was discharged with her twin sister.

The patient had unremarkable health maintenance visits at 1 and 3 weeks of age. At 7 weeks, she was evaluated by your partner for an erythematous, maculopapular, scaling rash on the face and shoulders. Hydrocortisone 1% cream was prescribed for presumed seborrheic dermatitis, and the rash resolved after one week. She had no further medical concerns until that 2-month-old visit. At each visit, weight was at the 10th percentile for postconceptual age.

Differential diagnosis of inguinal mass in an infant

The patient takes no medications at the moment, has no known drug allergies or exposures to animals or insects, and has not traveled outside her home city. Her mother confirms a negative family history of inguinal hernia, malignancy, immunodeficiency, and lymphoproliferative disorders. The girl's twin sister has had no medical problems.

You suspect that the inguinal mass may be something other than a simple reactive lymph node that arose from candidal dermatitis. Although it has the feel of an enlarged lymph node, its persistence and gradual growth over the past four weeks—despite resolution of the rash—is somewhat unusual.

You consider possible causes of isolated inguinal lymphadenopathy:
reaction to infection of the inguinal area or lower extremities by various pathogens
bacterial infection of the lymph node itself
malignancy, including lymphoproliferative disorders
an immunodeficient state
an infiltrative process

You are reassured that many of these potentially serious conditions are quite rare in young infants and most often present with generalized, rather than localized, lymphadenopathy. You also wonder whether the mass is truly a lymph node. Its proximity to the inguinal canal suggests herniated bowel, omentum, or, even, an ovary. Femoral artery aneurysm is also a consideration, although an unlikely one because the mass is nonpulsatile. Last, you keep in mind other soft-tissue masses, such as fibroma and neuroma.

Pictures don't lie
Faced with a large differential diagnosis, you decide that imaging may narrow your focus or even identify the problem definitively. You discuss the case with the medical center's pediatric radiologist and together decide that ultrasonography (US) would most likely provide useful information, and would also have the benefits of quick performance and low risk.2 Good fortune! There's time in today's radiology schedule to perform the study.

The baby heads off to the radiology suite with her mother. Twenty minutes later, the radiologist calls you back. The sonogram revealed an indeterminate, well-defined hypervascular mass in the region of the inguinal canal. The right ovary could not be visualized, but the mass doesn't resemble normal or enlarged ovary, bowel, or adenopathic tissue. The radiologist recommends that you strongly consider herniated omentum—even though a lymph node or herniated ovary cannot be excluded.

As you wait for your patient to return, you contemplate what to do next. The sonogram suggests a hernia but she has no history of intestinal symptoms, no findings of acute abdomen on exam, and no tenderness in the mass. This may not be a surgical emergency, but you're uneasy about the persistence and gradual growth of the mass over almost a month's time.

You reason that, because US could not definitively identify the mass, evaluation by a surgeon may be warranted sooner rather than later. By the time she returns, you've arranged an appointment in the pediatric surgery clinic later that week.

Time to go inside Two days pass. You take a call from the surgeon, who is as perplexed as you are. He has decided to admit the girl that evening for exploratory surgery. His thinking is similar to yours: The preoperative differential diagnosis favors hernia with entrapped ovary versus lymphadenopathy. Preoperative lab tests, including a complete blood count, comprehensive metabolic profile, and coagulation panel, have already been performed, and all results are within normal limits.

Later that day, the surgeon pages you at home. Exploration of the right inguinal area revealed no hernia, and he removed a single large lymph node. Your patient tolerated the procedure well and was discharged home from the recovery unit. The excised node has been sent for histopathologic analysis.

[Alon]

Bumpy ride ahead?
Ten days later, you receive the pathology report. Analysis of the lymph node revealed a paracortical histiocytic infiltrate with antigen markers indicative of an immature dendritic cell tumor, or early-stage Langerhan cell histiocytosis. The mass did hide something sinister after all! Although the report confirms your suspicions, you still have questions about the disease and the prognosis.

You discuss the patient's history with the pediatric oncologist who participated in the analysis of the node. He proposes, in retrospect, that the earlier facial and inguinal rashes may have been transient cutaneous manifestations of histiocytic disease. He further explains that excision of the lymph node may have been curative and that chemotherapy isn't indicated. Full-body imaging is necessary, however, to detect any occult tumors or skeletal lesions. He also recommends periodic close follow-up at your office and with the staff of the oncology clinic.

Langerhan cell histiocytosis (LCH) is a disorder of abnormal dendritic cell proliferation characterized by the presence of pathologic Langerhan cells (a type of dendritic cell, or histiocyte) within the centers of proliferation. Once known as histiocytosis X, LCH is a disease of diverse clinical presentations that encompass several conditions once thought to be distinct pathologic entities, including:
eosinophilic granuloma (localized bone lesions)
Hand-Schuller-Christian disease (multiple organ involvement characterized by a classic triad of skull defects, diabetes insipidus, and exophthalmos)
Letterer-Siwe disease (visceral lesions involving multiple organs)
Hashimoto Pritzker variant (congenital skin lesions that may resolve by 2 or 3 months of age but can recur).

Other histiocytic disorders feature proliferation of cell types other than the Langerhan cell, such as hemophagocytic lymphohistiocytosis (HLH), histiocytoma with macrophage phenotype, and Rosai-Dorfman disease (benign painless cervical lymphadenopathy with occasional extra-nodal involvement).3 Although LCH is the most common form of childhood histiocytosis, it is rare, affecting only one in 25,000 children annually.

The initial clinical presentation of LCH is varied and depends on the organ systems involved. In single-system LCH, only one organ or tissue is affected. For example, skin rash is the only manifestation in approximately 10% of cases. The rash often appears on the scalp and in flexural areas as reddish papules that progress to vesicles, pustules, or ulcers, followed by depigmentation and, eventually, healing. Often, the rash is mistaken for seborrheic dermatitis in newborns and infants.

LCH can also present as disseminated disease that affects multiple organs and tissues. Osteolytic bone lesions, manifesting as painful swelling, are present in more than 80% of cases. Other affected organs can include bone marrow, liver, spleen, lung, the central nervous system, and, more rarely, the gastrointestinal and genitourinary systems. Lymph node enlargement occurs in only 10% of cases, usually at initial presentation.

When LCH—in any form—is suspected, guidelines recommend a comprehensive workup of chest radiography and a skeletal survey, CBC, coagulation studies, and a liver function panel. A bone scan or body computed tomography scan may be helpful in certain cases. Definitive diagnosis requires biopsy and histopathologic analysis of a suspected lesion. Hallmarks of LCH include positive staining for the histiocytic markers CD-1a and S-100, as well as the presence of the Langerhan cell organelle, or Birbeck granule, within pathologic histiocytes.

Management of LCH depends on the extent of organ system involvement. Mild cutaneous disease may require only close observation or treatment with local corticosteroids. Severe cutaneous disease or multisystem disease may require extensive chemotherapy. Outcome correlates well with extent of disease involvement: Patients whose disease is more disseminated at presentation are at greater risk of relapse and death.

When do you watch the big picture? Your patient's case illustrates the challenge faced by a primary care provider when addressing common complaints with a wide differential diagnosis. Although careful history-taking and physical examination are often helpful in narrowing possibilities, potentially lethal rare diseases such as LCH may, in an early stage, offer few, if any, clues to help distinguish them from more common, less serious conditions. Our recommendation is not to be overzealous in pursuing zebras but to give thoughtful attention to the big picture when a constellation of symptoms evolves over time, and to take every opportunity to re-evaluate the differential diagnosis.

How quickly should workup of a suspected unusual condition proceed? In the case of your patient, the decision to send her for prompt surgical evaluation arose from two critical factors: persistence and gradual enlargement of the mass over more than one month despite resolution of the perineal rash and the inability of US to definitively identify its nature or visualize the right ovary.

Plan of observation You call the baby's mother to deliver the news. She is alarmed to hear "tumor" but relieved that the disease may have been cured by the surgery. You prepare the family for her upcoming visit to the oncology clinic. Information offered by the oncologist proves helpful as you carefully explain the details of the diagnosis and address her mother's concerns.

The family returns two weeks later for the twins' 4-month-old health maintenance visit. Your patient has done well since her operation and has no complaints. Her sister remains healthy too. The physical exam is unremarkable—you find neither a rash nor lymphadenopathy. She has had her first oncology clinic appointment and has undergone several imaging studies since you saw her last. A skeletal survey showed no bony lesions, and a full-body CT scan revealed only five small pulmonary nodules on the right side, suggesting asymptomatic pulmonary histiocytic disease. There is no remaining evidence on imaging of the left-sided inguinal nodes that you observed. Repeat lab tests were normal. The baby will alternate seeing you and then the oncologist at least once a month, and she will undergo serial imaging study and lab testing every three months. If she remains symptom-free from her knotty problem—if things go smoothly now!—the frequency of visits and testing may, gradually, decrease over time. Although the oncologist does not believe that the twin sister is at elevated risk of LCH, you will monitor her for clinical signs of disease at her well-child visits.

DR. FINK is a third-year resident in pediatrics, and DR. SERWINT is director of pediatric resident education and associate professor of pediatrics, both at Johns Hopkins University School of Medicine, Baltimore.

[Alon]

"That ever this should be!" The cellulitis that would not go away
The next patient waiting to be seen at your office today is a previously healthy 2-year-old girl who, according to her father when he called for an appointment, developed a "pimple-like" swelling on the lateral aspect of her right middle finger three days ago. Now, he tells you that he expressed "green fluid" from the lesion, and that erythema developed around it over the following two days. You examine the lesion, offer a diagnosis of cellulitis, and promptly begin treatment with amoxicillin-clavulanic acid.
"Full many shapes ... in crimson colours came"
Within one week of that office visit, however, the family notes progression of the process: Red streaks extend to the base of the middle finger, where a firm nodule develops. Despite multiple antibiotic changes that you institute—cephalexin, ceftriaxone, cefadroxil—the girl's condition does not improve over the ensuing four weeks.
You decide that the best course now is to consult an infectious disease specialist. A radiograph of the hand is taken and read as normal, excluding the possibility of chronic osteomyelitis. The consultant is concerned about the presence of an unusual, or resistant, organism. She institutes a trial of clindamycin but does not obtain material for culture, while you arrange referral to a plastic surgeon to have a biopsy performed.
"I fear thy skinny hand!"
At admission for biopsy, the parents confirm the absence of fever throughout the girl's illness. She has been acting well, they report, and has not had other skin lesions on the affected finger, including vesicles or puncture wounds by a thorn, or any musculoskeletal problems. The medical history includes infrequent episodes of otitis media and well-controlled atopic dermatitis. She does not take medications other than the antibiotics you recently prescribed. Immunizations are current. She is not allergic to medications.
The family reports that they have a pet cat but deny that the girl has been bitten or scratched by the animal. The family, including your patient, has not traveled outside the northeastern region of the United States or visited a farm in recent months. The girl has no known exposure to plants or moss, or to a person with tuberculosis. The family history is negative for chronic infection, immunodeficiency, and recurrent skin infection. One parent and one sibling have atopic dermatitis and food allergy. The patient is developmentally normal.
When you examine the girl, who is sitting on her mother's lap, she is somewhat apprehensive but does not appear to be in acute distress. She easily engages in conversation and play, and uses her right hand with little evidence of discomfort. You record vital signs: temperature, 36.2°C; heart rate, 112/min; respirations, 22/min; and blood pressure, 85/55 mm Hg. She is at the 25th percentile for height and weight for her age.
The physical exam is unremarkable except for the known findings on the right hand. The middle finger of that hand is swollen and erythematous but nontender. There is also as a pea-sized nodule in mid-dorsum on the right hand.
"Now wherefore stopp'st thou me?"
You consider the diagnostic possibilities—infectious and noninfectious. An osteoid osteoma of the finger, you recall, may not be painful and is not associated with fever. Ewing sarcoma and osteosarcoma typically do not occur in toddlers, and it is the long bones that are most often involved. Because of the girl's multiple lesions and the nonworrisome radiographic findings, you conclude that neither a benign nor a malignant tumor of bone is likely.
More and more, you are convinced that this patient has an unusual infection. (More and more, you feel like that Ancient Mariner of epic poetry—your search for a diagnosis like his voyage across a sea of unusual and inexplicable creatures and unexpected occurrences in "The Rime of the Ancient Mariner." Would the hero of Samuel Taylor Coleridge's puzzling 18th-century work know just how you feel as you confront this challenging investigation?)
You begin with a more mundane undertaking, however, by considering the most common organisms associated with cellulitis in an immunocompetent host. Staphylococcus aureus and Streptococcus pyogenes are the most common bacterial causes of cellulitis and osteomyelitis in children; methicillin-resistant S aureus should be considered, given its recent increase in incidence in children. Streptococcus pneumoniae and Haemophilus influenzae can cause facial and buccal cellulitis but probably not a hand cellulitis. Pasteurella multocida and Bartonella henselae are associated with cat bites and scratches. You even find cases in the literature of tularemia related to a cat bite. All these pathogens will need to be considered.
Now, what about infection with a more unusual organism? Cutaneous anthrax is commonly characterized by an eschar, absent here. As you think about the pattern of a line of nodules with erythema, you consider that the infection may fit the category of nodular or sporotrichoid lymphangitis—except that the nodules do not extend very far up her hand. Nocardia species are present in soil, and traumatic inoculation can cause this type of nodular cellulitis in a normal host. Sporotrichosis (caused by Sporothrix schenckii) is transmitted from plants (especially those with thorns), moss, and hay through small breaks in the skin; ulcerations of painless bumps are typically noted within three weeks of the onset of symptoms. Mycobacterium marinum can produce this picture after exposure to an aquatic environment.
As you are about to begin your investigation of possible uncommon sources of infection, the ID specialist heads out of the patient's room and stops you. She is smiling.

[Alon]

"As I was leaving the room," she says, "I said to her parents, 'I have one more question. Do you have a fish tank?' Mom replied, 'No. But we have a fish bowl. She helps us clean it every weekend.'"
"Yea, slimy things did crawl with legs"
The consultant orders a battery of laboratory tests, including a complete blood count. The white blood cell count is 11.4 X 103/mL, with a differential count of 39% polymorphonuclear neutrophils, 50% lymphocytes, 9% monocytes, and 2% eosinophils; hemoglobin, 12.3 g/dL; platelets, 343 X 103/mL. The C-reactive protein level is 0.1 mg/dL.
Biopsy of the skin in the affected area reveals a focal area of necrosis that is consistent with acute and chronic inflammation. A Gram stain is negative for bacteria, with 3+ polymorphonuclear neutrophils. Acid-fast staining is weakly positive for bacilli. Specimens are taken for bacterial and fungal cultures.
Those cultures eventually return negative. However, the acid-fast culture grows Mycobacterium marinum—and that jibes with the parents' comment about their fish bowl! The organism is sensitive to clarithromycin, rifampin, trimethoprim-sulfamethoxazole, and minocycline. The ID specialist is still smiling!
A course of clarithromycin and rifampin is started and, initially, the finger appears to improve. Approximately one month later, however, the nodule at the base of the finger enlarges and continues to do so. A three-month course of antibiotics ensues, but does not succeed in eliminating the nodule. The girl undergoes incision and drainage. Staining of material from the nodule reveals rare acid-fast organisms. A culture no longer grows M marinum, however.
She continues antibiotic therapy for a total of six months. One year later, your patient continues to do well and has no problem with recurrence.
"I fear thee, ancient Mariner!"
Like all Mycobacterium species, M marinum resides in macrophages. Hosts sequester the pathogen in granulomas, leading to long-term infection. M marinum infects fish and frogs, and was first isolated in saltwater fish in a Philadelphia aquarium in 1926. In 1951, the organism was identified in humans. The great majority of diagnoses are associated with fish tank, lake, pond, and swimming pool exposures. The annual incidence is 0.27/100,000 persons.
M marinum infection is most often limited to skin, where manifestations develop eight to 30 days after exposure at a site of minor skin disruption. Erythematous papules, nodules, or plaques erupt with or without purulent drainage. Infection may extend proximally in a nodular pattern. Although complications are unlikely, tenosynovitis, arthritis, bursitis, and osteomyelitis have been reported; disseminated infection is rare in an immunocompetent host. Treatment is based on the extent of disease. Generally, a prolonged course of an antimicrobial agent is administered. Surgical debridement may also be required for treatment to be effective.
In fish, M marinum infects numerous organs, resulting in a wasting syndrome, nodular lesions, ulceration and loss of scales, necrotic fins, discoloration, and rapid breathing. Because 25% of cases of M marinum infection occur in people who work with aquariums, a recent survey examined fish sales representatives' knowledge of M marinum infection (so-called fish tank granuloma) and their strategies for preventing infection. Of 40 salesmen, only six reported that they "knew the disease well"; 30 said they "knew about it, but ignored it." Thirty-three percent were introduced to the condition during their training to become an aquarium worker. Only eight were "concerned about human disease"; three of those had acquired an infection and five knew someone who had. Importantly, the majority of sales representatives immersed their ungloved hands in fish tanks daily, admitting that they discount the importance of fish tank granuloma.
"Water, water, everywhere"
When you see a patient with an erythematous skin lesion and fever, think of a staphylococcal or streptococcal infection first, of course, and treat the patient appropriately. In this time of increasingly common MRSA infection, remember to obtain material for culture whenever possible (see "Fighting a rising tide of MRSA infection in the young"). But if your patient fails to improve as expected, or if fever is absent, move to clarify the history and consider unusual organisms. That might help you swim toward the correct diagnosis—"alone on a wide wide sea!"

DR. YOUTH is director of the pediatric residency program at The Barbara Bush Children's Hospital at Maine Medical Center, Portland, Maine, where DR. JEWELL is a pediatric hospitalist and DR. MCCARTHY is director of the division of pediatric infectious diseases.

[Alon]

Delayed growth and sexual development in a 15-year-old: A rose by any other name

By Jane C. Lee, et al

The 15 1/2-year-old seated in your office is obviously uncomfortable. He has been referred for evaluation by his physician because of decreased growth and failure to develop secondary sexual characteristics, or, as he puts it, "not developing like the other boys." A copy of his growth chart has been sent along with the consultation request. Growth had been along the 75th percentile until age 10 years, with a rather dramatic decrease to the 5th percentile occurring in the last five- and-one-half years. The weight curve has been less affected.

According to Mother, the birth history is unremarkable and her son achieved normal developmental milestones. His past medical history is noteworthy only for a right-sided inguinal hernia repair at age 8 years. He is taking no medications and, except for growth and development, his health has been good. There is no history of unexplained fevers, abdominal pain, diarrhea or constipation, rashes, or exercise intolerance.

The family history is reviewed carefully. The young man has three siblings: two older sisters, both of whom had normal pubertal progression and growth with regular menses, and one prepubertal, healthy, 10-year-old sister. Mother is 5 feet 2 inches tall and reports menarche at 13 years. Father is 5 feet 9 inches, but his developmental history is unknown.

On physical examination, the youngster's vital signs are normal. His height, 158 cm, and arm span are the same, although the upper-to-lower body segment ratio (height minus the distance from the symphysis pubis to the floor) is 0.82; a normal ratio is >0.9. He appears healthy but younger than his age. Moderate gynecomastia is present. There are no signs of secondary sexual characteristics, including axillary hair, acne, or body odor. He is Tanner stage 2 for pubic hair and has a bilateral testicular volume estimated to be 2 cm3. His stretched penile length is 4.5 cm by 3 cm, clearly prepubertal. The neurologic examination is unremarkable, including normal visual fields.

The history and physical examination substantiate the delayed growth and sexual development but do not provide an obvious answer to the cause. The onset of puberty in males in the United States is 9 to 14 years, so this young man is clearly beyond the norm. In the general population the incidence of delayed puberty is less than 1%, with less than 2% of 14-year-old males and just 0.4% of 15-year-old males remaining prepubertal.

The first sign of pubertal development in males is scrotal reddening and thinning, followed by testicular enlargement to more than 2.5 cm in the longest axis, clearly not present here. This youngster's early pubic hair development is perhaps related to androgens produced by the adrenals, since the testes appear to be underdeveloped. It is clear that a further assessment needs to be performed.

Sniffing out the likely causes

As you complete the physical examination you consider the diagnostic possibilities and plan for evaluation. The young man's medical history has disclosed no evidence of chronic illness, head trauma, or nutritional disorders or other quirks. The mother's and sisters' pubertal progressions seem normal, and, although the father is unavailable, mother recollects no known unusual history in that sphere. Constitutional delay, the most common cause of pubertal delay, seems unlikely given growth at the 75th percentile until age 10 years. Children with constitutional delay usually demonstrate a slowing of linear growth during the first three years of life, with subsequent growth below but parallel to the 5th percentile. And, there is often a family history of pubertal delay, which does not appear to be the case here. Nevertheless, although the growth pattern is not typical, constitutional delay cannot be excluded entirely.

Could the cause be primary testicular failure? The testes are certainly small enough. Disorders in this group, also known as hypergonadotropic hypogonadism, are characterized by elevated levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in the serum. Failure to produce testosterone results in the overproduction of these gonadotropins because of a lack of feedback to the hypothalamic-pituitary axis. Primary testicular failure may be congenital, as with Klinefelter syndrome (46 XXY), or acquired, as with viral orchitis (mumps or Coxsackie B viruses) or iatrogenic causes (radiotherapy or chemotherapy).The latter seem unlikely, but Klinefelter syndrome may be on the list of possibilities. The young man does have somewhat eunuchoid proportions.

Could the problem be central? Perhaps there is a hypothalamic or pituitary cause, disorders that fall into the category known as hypogonadotropic hypogonadism. The deficiencies in gonadotropins may be absolute or partial, congenital or acquired (sarcoidosis and head trauma, for instance), functional (related to exercise, anorexia, or anabolic steroids) or structural (craniopharyngioma or germinoma). Then there is the ever present idiopathic (we don't know the cause) isolated gonadotropin deficiency and Kallmann syndrome. Hmmm.... Kallmann syndrome. Hypogonadism associated with lack of the sense of smell!

Take time to smell the roses

The history is not complete. You turn to the youngster and ask, "How do you like the smell of roses?" He looks startled and replies, "What do you mean?" Mother suddenly interjects that her son douses himself with cologne. He protests, but then admits that he really cannot smell well.

The simple question and response provides direction for an evaluation. Gonadotropins are ordered and a magnetic resonance imaging study of the brain is scheduled.

The serum gonadotropins are appropriate for Tanner stage 2 of sexual development, but the levels are not appropriate for the young man's chronologic age, which should be in the Tanner 4 or 5 range. The levels reflect hypogonadotropism. The MRI scan report supports your diagnostic suspicion: absent left olfactory sulcus, hypoplastic right olfactory sulcus, and a small pituitary gland, findings consistent with Kallmann syndrome!

Mastre de San Juan, in the mid-19th century, first described the anatomic association between absent olfactory lobes and underdeveloped genitalia in a male with sexual infantilism.Kallmann and Schoenfeld later attributed a genetic basis to this disorder when they observed three families with the condition. DeMorsier is credited with noting the association of hypogonadism and anosmia with agenesis of the olfactory bulb, which he named olfactogenital dysplasia.

Kallmann syndrome is an uncommon disorder with a prevalence of 1 in 10,000 live births and with a male to female ratio of 3.9 to 1.3 Isolated GnRH deficiency may occasionally be detected in the neonatal period when an infant presents with cryptorchidism and microphallus. More typically, GnRH deficiency presents in adolescence when secondary sexual characteristics fail to develop. Unlike patients with constitutional delay, children with Kallmann syndrome may have normal height until adolescence, when they fail to manifest a growth spurt. Eunuchoid proportions are common, with arm spans typically 5 cm greater than height, and upper-to-lower segment ratios less than 0.9.

Impairment of smell may be partial (hyposmia) or complete (anosmia) in this syndrome. Neither patients or families may notice the impairment, especially when the defect is not complete. Testing with graded dilutions of pure scents is necessary to determine a defect in the sense of smell.Affected individuals are still able to smell irritants such as smoke and skunks, however.

Individuals with Kallmann syndrome may have associated physical and neurologic abnormalities, including cleft lip and palate, imperfect facial fusion, sensorineural deafness, cerebellar ataxia, oculomotor abnormalities, and seizure disorders, among other findings.

The most common form of Kallmann syndrome appears to be inherited in an X-linked pattern, although autosomal recessive and dominant forms have been described. Genetic linkage studies have localized the X-linked form to the so-called KAL gene on Xp22.3, which codes for an adhesion molecule that allows olfactory neurons expressing gonadotropin-releasing factor to migrate to the brain from the olfactory placode.Interestingly, there is considerable heterogeneity in families with this disorder. In the same family, some members may have gonadal deficiencies without loss of smell and others may have loss of smell without abnormalities in gonadal function.

How often do we ask about the sense of smell during routine office visits? Not often. But, given an adolescent with pubertal delay and small testes, you have the chance of smelling like a rose if you ask and discover that the youngster lacks function of cranial nerve I!

[Melnichenko]

У 35 летней женщины с первичной аменореей при первом опросе наш врач выяснил,что она вообще не различает запахи :" Не могу отличить. пахнет ли бензином или жаренной картошкой, все удивляются " . Удивляются минимум 20 лет - все знакомые, все врачи...

[Alon]

Сообщение от Melnichenko

У 35 летней женщины с первичной аменореей при первом опросе наш врач выяснил,что она вообще не различает запахи :" Не могу отличить. пахнет ли бензином или жаренной картошкой, все удивляются " . Удивляются минимум 20 лет - все знакомые, все врачи...

Вообще-то алгоритм простой. Удивился - открыл книгу.
А это что-то многовато будет.
Но наверняка красавчики продолжают работать и продолжают удивляться.
А потом мы удивляемся.

[Alon]

Sore throat, fever, intensifying malaise and abdominal pain: Will le diagnostic escape you?

Sunil K. Sood et al

One of your patients, a 16-year-old boy who's been healthy until now, was brought to the ED earlier today, you are informed, complaining of three days of throat and abdominal pain, fever, and swelling of the neck.

The ED physician goes on to describe that she found abdominal tenderness and erythema of the oropharynx but that her exam was otherwise unremarkable. Lab test results show anemia (hemoglobin, 11.9 g/dL); thrombocytopenia (platelet count, 90 X 103/?L) and hyperbilirubinemia (total bilirubin, 4.3 mg/dL; direct bilirubin, 1.4 mg/dL). Liver function tests are normal. A throat culture for group A Streptococcus, a hepatitis panel, and a heterophil antibody assay for Epstein-Barr virus (EBV) have been ordered, but the patient is being released before results are returned because he appears otherwise well. His parents have been told to follow up with a visit to your office tomorrow.

The next day, before your patient arrives, you check on those pending test results. The heterophil antibody assay is negative, as is the hepatitis panel. But you're not feeling very enlightened: The heterophil assay can be negative in early EBV disease and, with liver function normal, hepatitis is unlikely, anyway.

In walks your patient, looking tired but not in distress. You confirm the history; on the physical exam, you note scleral icterus and a swollen submandibular lymph node—but nothing else. You order an EBV serologic study and a Coombs' test but, because he looks well, you send him home once again, with a presumptive diagnosis of early EBV infection as the cause of the throat pain, lymphadenopathy, scleral icterus, and splenomegaly.

Mais il retourne!

But the following day, the boy's parents call your office. They are increasingly concerned. His abdominal pain has become worse, they tell you, he can no longer tolerate even fluids, and the fever continues. And he is feeling more and more lethargic. Uncertain how to proceed, you direct them to bring the boy back to the ED, where you will meet them, for further evaluation.

When you meet the family at the hospital, the boy—now on day 5 of symptoms—appears tired. Vital signs are stable. The physical exam is significant for an erythematous oropharynx, scleral icterus and, now, enlarged, right-sided, submandibular, matted lymph nodes. You note abdominal tenderness upon palpation of the right upper quadrant, without guarding or hepatosplenomegaly. Reflecting on the earlier test results, you send off for new blood tests and are surprised by the continuing presence of anemia (hemoglobin, 10.6 g/dL); thrombocytopenia (platelets, 67 X 103/?L) and hyperbilirubinemia (total bilirubin, 7.4 mg/dL; direct bilirubin, 4.2 mg/dL). Blood is drawn for culture.

You decide to admit the boy to the pediatric floor for rehydration and further workup of this intriguing constellation of symptoms. Throughout the day, the fever continues and he begins to have intermittent episodes of shaking chills. The chills abate soon enough, but the patient continues to look ill and the diagnosis remains a mystery.

You step back to consider where things stand. Infectious mononucleosis can certainly prompt this presentation, but EBV titers and the heterophil assay were completely negative. Hepatitis can present this way, but the history and test results are inconsistent. Could this be an autoimmune hemolytic anemia? That's doubtful: The Coombs' test was negative. And how to explain the progressive abdominal pain?

ID will think of something (peut-?te) At this point, after so much physical inspection of no conclusiveness, you seek a subspecialist's opinion. The intern doing an infectious disease elective examines the patient. Afterward, in presenting the case to the ID attending physician, she reports that what has been described as enlarged submandibular lymph nodes is, in her estimation, a tender neck mass under the mid-sternocleidomastoid muscle.

The ID attending has a hunch! He rushes in to palpate the patient's neck, and confirms his speculation. He tells the mystified floor resident, "Order a neck CT and you'll have your diagnosis."

[Alon]

Merveilleux pour voir—c'est le diagnostic!

Computed tomographic scanning of the neck reveals thrombosis of the right internal jugular vein consistent with a diagnosis of Lemierre syndrome, also known as necrobacillosis and postanginal septicemia.Intravenous clindamycin and ceftriaxone are started and the patient is transferred to the pediatric intensive care unit because of developing dyspnea and pleuritic chest pain, and to allow closer observation. Contrast-enhanced CT of the chest performed later showed multiple small nodules consistent with pulmonary septic emboli.

Lemierre syndrome (LS) is characterized by an oropharyngeal infection that is followed by jugular vein thrombophlebitis and subsequent metastatic emboli. LS was first described by Courmont and Cade in 19002 but, in 1936, was named after the French physician Andre Lemierre, who reviewed 20 cases of the syndrome3—of which eight had a fatal outcome seven to 15 days after onset of symptoms.

The oropharynx is the primary site of infection in most cases of LS, although parotitis, otitis media, mastoiditis, sinusitis, and odontogenic infection have all been implicated as underlying sources of the infection.LS is most often caused by Fusobacterium necrophorum, a member of the normal flora of the oral cavity and, to a lesser extent, of the gastrointestinal tract and the female genital tract. (A pathogen was not isolated in this case, most likely because initial blood cultures were not inoculated in an anaerobic bottle.) F necrophorum is an obligate anaerobic, gram-negative bacillus that can become invasive in previously healthy adolescents and young adults. Virulence is attributed to production of lipopolysaccharide endotoxin and exotoxins, such as leukocidin, hemolysin, lipase, and cytoplasmic toxin. Other pathogens are also implicated in LS: species of Streptococcus, Bacteroides, and Peptostreptococcus, and Eikenella corrodens.

Why does F necrophorum become invasive in some healthy persons and lead to LS, as it did in your patient? The reason is unclear, but alteration of the oropharyngeal mucosa during prior viral infection may be a major factor. Signs and symptoms of LS are a consequence of infection of the parapharyngeal space, which is divided by the styloid process into anterior muscular and posterior neurovascular compartments. Involvement of the anterior compartment results in neck pain and swelling below the angle of the mandible (as seen in your patient), trismus, and dysphagia. Infection of the posterior compartment at the location of the internal jugular vein causes complications, such as thrombophlebitis and severe sepsis with metastatic emboli, most often to the lungs.

Other possible sites of embolic disease include the liver; joints, leading to septic arthritis and osteomyelitis; bone marrow, causing infarcts and pancytopenia; kidneys, leading to transient hematuria and an elevated serum creatinine level; and, seldom, the brain, resulting in meningitis. Pyomyositis, hepatosplenomegaly with abscess and a slightly elevated level of liver enzymes, and mild hyperbilirubinemia as a result of a direct toxic effect on the hepatobiliary system have all been described in conjunction with LS.

How would you suspect this diagnosis the next time around? Think of LS in a febrile adolescent who has non-improving pharyngeal pain or a biphasic course. You'd make a tentative diagnosis of LS on clinical grounds—recall this patient's presenting complaints of fever, neck and abdominal pain, jaundice, and chills—and order a contrast-enhanced CT scan of the neck, chest radiograph, and blood cultures in aerobic and anaerobic bottles. F necrophorum can sometimes be cultured from the metastatic site of infection.

Doppler ultrasound is the most commonly used—and the preferred—modality for evaluating internal jugular vein thrombosis because it is less expensive and less invasive than imaging studies. Some experts assert that contrast-enhanced CT is the imaging method of choice because of its superior sensitivity. Still others recommend magnetic resonance imaging for evaluating internal jugular vein thrombosis, calling it superior to other diagnostic modalities because it is even more sensitive and provides soft-tissue contrast without contrast or radiation. Metastatic infection can be diagnosed with a chest radiograph to document pulmonary septic emboli and with abdominal ultrasonography or high-resolution CT (or both) to look for hepatic or splenic involvement.

The primary treatment of LS is antibiotics. Although all isolates in a recent report from Wisconsin were ? lactamase-negative, resistance is often reported, and most experts recommend ? lactamase-resistant antibiotics with anaerobic activity. Appropriate choices are: clindamycin, ?-lactam and ?-lactamase combinations (ticarcillin-clavulanate, ampicillin-sulbactam), metronidazole, and a carbapenem.

Some authorities recommend anticoagulation when septic emboli do not resolve with antibiotic therapy, or when evidence exists of internal jugular vein thrombi propagating to the cavernous sinus, or both. The duration of anticoagulation is generally no longer than three months. Other potentially appropriate treatments include surgical drainage of soft-tissue abscesses and suppurative fluid collections and surgical ligation of the internal jugular vein when septic emboli persist despite appropriate antibiotic treatment.

As for this patient, he was discharged on oral clindamycin to complete a six-week course of antibiotics. He was also started on IV heparin and discharged on oral warfarin for a total of three months because of persistent small lung opacities that were presumed to be sterile resolving emboli. The boy recovered completely and was weaned from warfarin without sequelae.

Lemierre syndrome had become uncommon in the antibiotic era. Yet an increase in its incidence has been noted in recent years—perhaps as the use of antibiotics to treat nonstreptococcal pharyngitis has declined. We generally think of throat and neck pain in an adolescent as harmless—mais attention! LS remains a possible complication—and a rapidly progressive and potentially lethal one at that!

[Alon]

All in her head? Intermittent headache and vomiting in a 12-year-old

By Alyssa Harrison, MD

This 12-year-old girl is a rare visitor to your office. But today she's here, accompanied by her mother, with a complaint of headache and vomiting. The symptoms developed two weeks earlier, she reports, and have occurred intermittently since. Pain is localized to the occipital region but is occasionally bilateral frontal, occurs more often in the afternoon, and persists severely for five to 15 minutes and then dully thereafter. She doesn't complain of photophobia but does describe halos around objects, and tells you that colors "look weird" during headaches.

The patient had three episodes of vomiting on one day when the headache was present, two episodes on another. The vomiting was not self-induced, she insists, and was not associated with abdominal pain. She has not been awakened during the night or early morning by headache or vomiting; in fact, she reports, sleep relieves the headaches.

The girl cannot identify any triggers for the headaches, although her mother confesses to significant—but unspecified—family stress. Acetaminophen, the only medication that the girl takes, does not provide relief. She reports having had her first menstrual period two months earlier but not having one since.

The girl's medical history is vague. The mother recounts evaluation for rapid head growth in infancy, including a computed tomographic (CT) scan of the brain. There was a question of hydrocephalus at the time, but she was never treated surgically; the family was eventually reassured that follow-up was unnecessary. You perform a quick check of her head circumference: it's at the 98th percentile.

The family history reveals some interesting, perhaps relevant, information. Her mother has a history of migraine headache since 17 years of age, although symptoms subsided as she grew older. The mother's second pregnancy was complicated by birth defects, including hydrocephalus, and resulted in spontaneous abortion. The girl's father had congenital hydrocephalus that required placement of a shunt.

The physical examination shows you a well-appearing teenaged girl. Vital signs are normal, as is her general exam. No focal neurologic abnormalities are detected, and fundi show sharp disk margins.
Proceeding lacking clear direction

You consider the need for further work-up. Certainly, headache is a common complaint in children and adolescents, but rarely one that signals serious disease; clinical laboratory testing, electroencephalography, and brain imaging are usually uninformative. Are there features in this patient that prompt specific concerns? The visual aura, vomiting, and family history in the mother support classic migraine headache, although the occipital location and short duration are less typical. Recent stress could be the trigger for migraine or tension headache. You are most concerned about headache caused by intracranial pathology, however. It is reassuring to note that her headaches are marked by afternoon (as opposed to early morning) onset, that she has symptom-free intervals, and that the neurologic and funduscopic exams are normal.

Still, her uncertain history and strong family history of hydrocephalus create lingering doubt. Could macrocephaly in infancy be related to her current symptoms? You decide that brain imaging is indicated and order a CT scan of the head.

The patient and her mother—and you—are relieved to learn that the cranial CT is unremarkable. Confident that the headaches must be related to recent stress, they decline a trial of antimigraine medication. They agree to keep a headache diary and to return for follow-up in one month.
Two heads may not be better than one

At the next visit, you detect significant discrepancy between the history provided by the patient and her mother's account of her illness. Having failed to maintain a headache diary, the girl can only report that the headaches continue at a rate of least three times a week. Her mother disagrees: They're much less frequent. The patient insists that the pain is still severe (she rates most headaches at 8, on a scale of 1 to 10). General features of the headache are unchanged, although vomiting has completely resolved. But her mother disputes her, again, on the intensity of the headaches; she says she is sympathetic to her daughter's situation but is concerned that the girl is seeking secondary gain with her ongoing complaint. The mother's perception is that the headaches aren't incapacitating, occur at school only very rarely, and may allow her daughter to "escape" some of the conflict at home. You discuss this possibility further with mother and daughter, and all agree that counseling, with attention to stress management, should be initiated as soon as possible.
Milking the history

A long time passes before you see this patient again. She fails to keep several appointments. In a telephone conversation with you, her mother attributes the missed appointments to continued family stressors but reports that her daughter has generally been well.

Fifteen months later, the girl returns for a routine physical examination. Review of the time since her last visit reveals that the headaches have continued but are more easily tolerated. She does, however, have a new concern: Her first menses—reported longer than one year ago now—was the only one she experienced. She recalls that the vaginal blood flow on that occasion was scant and lasted only two days. She admits that she just assumed that her body "wasn't ready" to start menstruation, but now wonders aloud to you whether such a pattern—really, no pattern at all—is normal.

[Alon]

Breast development began more than three years ago; breasts and pubic hair are now Tanner stage IV. Growth has decelerated slightly (her height is at the 50th percentile for age) and weight has been steady at the 95th percentile. She has no complaint of hirsutism, acne, or galactorrhea. She denies cyclic abdominal pain, cold intolerance, constipation, change in skin or hair texture, decreased energy level, sexual activity, and taking medications or using illicit drugs or alcohol. She has pursued interscholastic sports, but not seriously.

She has no appreciable hirsutism, acne, striae, or acanthosis nigricans. Inspection of the external genitalia shows a normal vulva without clitoromegaly. A digital pelvic exam confirms a patent vaginal canal and palpable cervix. The only other change she notes is difficulty with vision during the past year. Indeed, although a prior vision screening examination yielded 20/20 acuity, her best effort at this visit demonstrates 20/100 acuity. Visual fields by confrontation seem normal.

The history of amenorrhea in this well-developed girl intrigues you, and you conclude that it deserves attention. A single episode of menses suggests normal anatomy, and you ponder the differential diagnosis of secondary amenorrhea. Is this symptom independent of her earlier complaint of headache, or is it related—somehow?
Down into the cellar for a diagnosis

You order tests of thyroid-stimulating hormone (TSH), luteinizing hormone, follicle-stimulating hormone (FSH), prolactin, dehydroepiandrosterone, and testosterone. TSH, gonadotropin, and testosterone levels are normal, but the prolactin level returns markedly elevated at 183 ng/mL (normal, 2.8 to 29.2 ng/mL). Dehydroepiandrosterone is also elevated at 14.8 ng/mL (normal, 1.5 to 7 ng/mL).

Magnetic resonance imaging (MRI) of the brain confirms your suspicion. A mass 0.8 x 1.2 cm is visualized within the left pituitary fossa. It does not appear to impinge on the optic chiasm, but does displace the left internal carotid artery and cavernous sinus. Reproductive endocrinologic and neurosurgical consultations are obtained and treatment for prolactinoma is initiated.

A prolactinoma is a benign tumor of the pituitary gland that leads to hypersecretion of the hormone prolactin. The tumor is rare in children compared to its prevalence among adults, although pituitary tumors do constitute approximately 2.7% of supratentorial tumors of childhood. In younger age groups, adrenocorticotropic hormone-secreting tumors are the most common pituitary adenomas, whereas prolactinoma predominates by adolescence.Girls are affected more often—by a ratio as high as 4.5:1—although prolactinomas are usually larger in boys by the time they are identified.

In addition to its lactogenic effect, prolactin may affect the hypothalamic-pituitary-gonadal axis. Presenting symptoms of prolactinoma reflect hyperprolactinemia or mass effect, and often include headache, arrested growth, and delayed puberty. In girls, amenorrhea or galactorrhea may be the initial complaint; boys may rarely demonstrate gynecomastia. Enlargement of the pituitary may cause compression of the optic chiasm, resulting in visual disturbances such as bitemporal hemianopia (tunnel vision).

Under normal circumstances, prolactin is secreted episodically from the pituitary gland and regulated by chronic dopamine inhibition, yielding a serum concentration of 1 to 20 ng/mL. Many physiologic and pathologic factors affect secretion of prolactin; stress, exercise, routine breast examination, a number of medications (phenothiazines, benzodiazepines, cimetidine, and metoclopramide, for example), and illicit drugs may cause a modest elevation. Hormonal changes of pregnancy, hypothyroidism, and polycystic ovary syndrome can also cause hyperprolactinemia. These clinical scenarios typically elevate the prolactin level to 30 to 100 ng/mL. Concomitant rise in dehydroepiandrosterone may occur as a result of prolactin receptors in the adrenal gland. A prolactin level >100 ng/mL suggests a prolactin-secreting tumor and should be further explored by brain imaging.

Because routine head CT may provide suboptimal images of the sellar region or lack the sensitivity to detect very small lesions, pituitary pathology is best defined by MRI. Once a prolactinoma is delineated radiologically, it is classified on the basis of its size as a microadenoma (<1 cm in diameter) or a macroadenoma (>1 cm). Size often correlates with the degree of hyperprolactinemia and may influence the approach to management.

Both microadenomas and macroadenomas must be treated if symptoms are to be relieved, normal menstrual cycles and fertility restored, and the patient protected from further complications. Because a microadenoma does not necessarily progress to a macroadenoma, the decision to treat is based on the clinical scenario. Direct extension of a macroadenoma poses an ongoing risk of loss of vision, destruction of the pituitary, and hypopituitarism—mandating more urgent need for treatment. In addition, most adolescents with a prolactinoma are estrogen-deficient and therefore suffer significant bone loss if not treated.

Dopamine agonist therapy has replaced surgery as the mainstay of treatment for adolescents with prolactinoma. Bromocriptine, once daily, or cabergoline, twice weekly, decreases the level of circulating prolactin, ultimately shrinking the tumor in most patients. Common side effects—including headache, nausea, and dizziness secondary to postural hypotension—are less likely when using newer, long-acting formulations of these drugs. Duration of therapy depends on the patient's response, although few prolactinomas are self-limited. Despite the striking reduction in the size of the tumor prompted by medication, it is never eliminated and lifelong pharmacotherapy is often required to sustain remission.

When a prolactinoma is refractory to medical management or a patient cannot tolerate dopamine agonist medications, then trans-sphenoidal surgery or, more rarely, radiation therapy may be required. These alternatives are avoided as first-line interventions because they carry a high risk of severe complications, especially in cases of macroadenoma.

It is essential to provide long-term follow-up for patients with prolactinoma. Routine monitoring of clinical status, measurement of the prolactin level, examination for visual field changes, and observation of the appearance of the tumor with MRI should be performed every three to six months during the initial phase of therapy. Especially close surveillance is needed during pregnancy and in the peripartum period. Dopamine agonist therapy is discontinued upon recognition of pregnancy, thereby increasing the risk that a macroadenoma will expand and related complications will develop.

Pituitary adenomas, including prolactinomas, are rarely fatal, but associated endocrinopathy may exert a profound effect on the patient's quality of life. Early evaluation and intervention are necessary to prevent permanent consequences of unrestrained tumor growth, especially during vulnerable periods of rapid sexual and skeletal development.

Pediatricians, and parents, often attribute headache to psychosocial stressors, particularly in adolescents, based on a consistent history and physical exam. This may often be true, but these patients should nevertheless be followed carefully for evolving symptoms or clinical changes that suggest an alternative cause. Before you conclude that the problem is all in the patient's head, consider this: It just might be.

[Melnichenko]

Здесь любопытна еще информация по ДЭАС и пролактину- пролактин рассматривается как один из потенциальных стимуляторов продукции стероидов - и как блокатор 5- альфа редуктазы. Поэтому как увеличение ДЭАС, так и отсутствие при этом существенных изменений оволосения- клинически банальная ситуация. В целом пролактиномы как причина первичной аменореи при наличии телархе и пубархе должны четко осознаваться практическими врачами.Очень хороший пример, спасибо.

[Alon]

Asymptomatic Inflammatory Bowel Disease Presenting With Mucocutaneous Findings
Sheila S. Galbraith et al.

Abbreviations: IBD, inflammatory bowel disease • 6-MP, 6-mercaptopurine • ESR, erythrocyte sedimentation rate

Inflammatory bowel disease (IBD) is a group of gastrointestinal disorders characterized by relapsing and remitting signs and symptoms. Intestinal manifestations such as abdominal pain, diarrhea, fever, weight loss, and extraintestinal manifestations including mucocutaneous lesions, iritis, and arthritis may be associated with IBD. Mucocutaneous lesions are relatively common during the course of IBD. Less commonly, however, they can be a presenting finding, thereby alerting the clinician to the diagnosis of IBD before the onset of gastrointestinal symptoms. We describe 9 children from 2 medical institutions in whom mucocutaneous lesions preceded abdominal manifestations and led to an early diagnosis of IBD.

Patient 1
A 6-year-old white boy presented with a 5-month history of intermittent upper-lip swelling associated with eczematous skin changes and gingival edema (Fig 1). Over the subsequent 3 years, he developed worsening of the upper-lip swelling as well as angular cheilitis and lower-lip involvement (Fig 2). He denied any systemic symptoms including facial paralysis, abdominal pain, and diarrhea. A biopsy specimen from the oral mucosa showed a hyperplastic mucosa with spongiosis and a dense lymphocytic infiltrate with small granulomas in the submucosa. Patch tests, complete blood count, tuberculosis skin tests, chest radiograph, and pulmonary function tests were within normal limits.
A repeat biopsy was planned because of lack of improvement with several therapies including topical steroids, antihistamines, amoxicillin-clavulanate, and minocycline for presumed Melkersson-Rosenthal syndrome. On returning to the clinic for biopsy, his mother mentioned a perianal pustule that had been present for some time. Given this new information, the oral biopsy was not performed; he instead was referred to a gastroenterologist. The patient was found to have microcytic anemia (hemoglobin: 11.1 g/dL; mean corpuscular volume: 75 fL) and hypoalbuminemia (3.3 g/dL) at that time. Esophagogastroduodenoscopy was unremarkable; however, patchy erythema, erosions, and pseudopolyps were seen during colonoscopy. Biopsies from the colon showed gastritis, terminal ileum granulomas, and granulomatous colitis, confirming the diagnosis of Crohn's disease.

The perianal lesion proved to be a fistula, and 6-mercaptopurine (6-MP) was started. Metronidazole was added intermittently to treat the fistula further. There was mild improvement of the granulomatous cheilitis; however, the fistula remained patent. Infliximab was started, with complete resolution of the oral lesions, closure of the fistula, and normalization of laboratory abnormalities after 3 infusions. He is in clinical and biochemical remission without intestinal or extraintestinal manifestations while maintained on scheduled 8- to 10-week-interval infliximab therapy.

Patient 2
An 8-year-old white boy had a 2-year history of recurrent oral ulcerations with hyperplastic ridges in the inferior gingival sulcus bilaterally (Fig 3). He denied any gastrointestinal symptoms. A previous oral biopsy was reviewed and showed a small granuloma in the submucosa. He also had a history of perianal skin tags and fissures. Gastrointestinal evaluation revealed esophagitis, gastritis, and multiple aphthous ulcers in the sigmoid colon. Biopsy specimens showed esophagitis with granulomas and granulomatous colitis consistent with Crohn's disease. Work-up subsequently revealed hypoalbuminemia (3.2 g/dL) and an elevated erythrocyte sedimentation rate (ESR) (32 mm/hour). Monotherapy with 6-MP resulted in resolution of his oral ulcers.
Patient 3
A 12-year-old obese white boy (body mass index: 97th percentile) presented with a 6-month history of an erythematous plaque on his right lower extremity that more recently had become warm to the touch, tender, and ulcerated with indurated violaceous borders (Fig 4). The patient denied any trauma to the area. Two biopsies performed elsewhere were consistent with folliculitis, and the patient had been treated with Augmentin and topical antibiotics with no improvement. Repeat biopsy showed suppurative folliculitis which, along with the typical clinical presentation, was consistent with pyoderma gangrenosum. Fungal culture and acid-fast bacillus stains were negative. His ESR was slightly elevated (14 mm/hour). The patient denied any gastrointestinal complaints, but upper and lower endoscopy showed multiple ulcerations in the gastric antrum and ileum. Biopsy specimens showed gastritis, ileitis, and crypt destruction with giant-cell reaction in the colon consistent with Crohn's disease. He initially received intralesional corticosteroids for the pyoderma gangrenosum; however, after the diagnosis of Crohn's disease was made, infliximab and methotrexate were initiated, which led to almost complete resolution of the pyoderma gangrenosum.

In our series of children with silent IBD, mucocutaneous lesions appeared before gastrointestinal signs as the manifestation of Crohn's disease (8 of 9) or ulcerative colitis (1 of 9). (Table 1 provides a summary of these cases.) Of the 9 patients, 8 were male, and the mean age was 8 years. Although patients with IBD tend not to be overweight, 2 of our patients were obese (patients 3 and 8). Six children presented with oral manifestations, 1 had genital lesions, and 2 had pyoderma gangrenosum. All patients were asked about gastrointestinal symptoms, fever, weight loss, and joint pain at presentation and denied any such symptoms. The majority of our patients (7 of 9) had perianal lesions at presentation; however, several of the perianal lesions were not discovered on initial evaluation but only became apparent during subsequent examinations. The time to diagnosis of IBD after development of the mucocutaneous findings ranged from 1 month to 42 months. In general, patients with oral and perianal lesions experienced a longer time until diagnosis compared with patients with lesions that presented elsewhere. One patient (patient 8) was diagnosed with Crohn's disease on repeat endoscopy after the initial endoscopy that was performed 1.5 years prior was normal. In all patients followed after instituting therapy, the mucocutaneous lesions responded to therapy for their IBD.