Index of Suspicion * Case 1: Leg Cramps, Hand Spasms, Diarrhea, and Substantial Weight Loss in a 12 Year Old * Case 2: Hypothermia, Hypoglycemia, and Hyperbilirubinemia in a Neonate * Case 3: Recurrent Fevers, Abdominal Pain, and Cervical Lymphadenopathy in a 7 Year Old

A 12-year-old previously healthy boy presents with leg cramps for 2 weeks and spasms of his hands since yesterday. He also complains of nausea, bloating, epigastric pain, and recurrent watery and loose stools for 1 month. Currently, he is taking lansoprazole for epigastric pain without any relief. He also has a history of involuntary weight loss of 10 lb over 2 months. The family history contains no findings of note.On physical examination, the boy's weight is 36 kg (25th percentile) and height is 140 cm (10th percentile) and he exhibits a positive Trousseau sign and negative Chvostek sign. Remaining physical signs, including on abdominal examination, are normal.Laboratory evaluation shows hypocalcemia (total calcium of 5.3 mg/dL [1.3 mmol/L], ionized calcium of 2 mg/dL [0.5 mmol/L], and corrected calcium of 6.1 mg/dL [1.5 mmol/L]) as well as hypoalbuminemia (3 g/dL [30 g/L]). Serum magnesium measures 1.6 g/dL. CBC shows Hgb of 9.3 g/dL (93 g/L), Hct of 29% (0.29), WBC count of 9.9×103/μL (9.9×109/L), platelet count of 471×103/μL (471×109/L), mean corpuscular volume of 67 fL, and reticulocyte count of 1% (0.01). Results of the iron studies are consistent with iron deficiency anemia, with a serum iron concentration of 6 μg/dL (1.07 μmol/L) (31 to 144 μg/dL [5.5 to 25.8 μmol/L]), transferrin saturation of 3% (0.3), and serum ferritin less than 5 ng/mL (11.23 pmol/L) (21 to 275 ng/mL [47.2 to 617.9 pmol/L]). ESR is 46 mm/h and CRP is 9.5 mg/dL (normal <0.05 mg/dL). His serum 25-hydroxyvitamin D concentration is low at 5.7 ng/mL (14.2 nmol/L) (normal, 32 to 100 ng/mL [79.9 to 249.6 nmol/L]) and serum parathyroid hormone, urine calcium, and creatinine values are within normal limits. His tetany and hypocalcemia resolve with calcium replacement. Additional evaluation leads to the diagnosis.A 1-month-old boy is admitted for evaluation of hypothermia and lethargy. He was born at 34 weeks' gestation to a G1 18-year-old woman following an uncomplicated pregnancy and delivery and had spent 1 week in the neonatal intensive care unit for transient hypothermia, hypoglycemia, and hyperbilirubinemia requiring phototherapy. The hyperbilirubinemia was attributed to breastfeeding and he was switched to formula feeding before discharge. A thorough evaluation for infection yielded negative results.Two weeks after discharge, he is readmitted for intermittent hypoglycemia. Home glucose meter readings range from 32 to 89 mg/dL (1.8 to 4.9 mmol/L), despite feedings of 3 to 4 oz every 2 to 3 hours. He has a rectal temperature of 35.2°C, scleral icterus, and jaundice to the lower abdomen. He does not have hepatosplenomegaly, and he has normal male genitalia.His serum glucose concentration is 36 mg/dL (2.0 mmol/L), total bilirubin is 13.3 mg/dL (227.5 μmol/L), and direct bilirubin is 3.1 mg/dL (53.0 μmol/L). Results of additional laboratory tests are as follows: negative full sepsis evaluation (blood, urine, and CSF cultures); negative urine and serum studies for cytomegalovirus; normal CBC, peripheral smear, and reticulocyte count; normal serum electrolyte values; nonreactive hepatitis A, B, and C studies; normal serum gamma glutamyl transpeptidase, total protein, albumin, alkaline phosphatase, ammonia, and lactic acid values; normal urine organic and amino acids; and normal plasma amino acids. Maximal concentrations of serum AST and ALT are 249 and 139 U/L, respectively. Abdominal ultrasonography yields normal results. Additional imaging and laboratory studies reveal the cause of his hypoglycemia, hypothermia, and hyperbilirubinemia.A 7-year-old boy is transferred from another facility to rule out lymphoma because of a 2-day history of temperatures up to 40.6°C and an enlarged posterior cervical lymph node. He does not have runny nose, cough, nausea, vomiting, or diarrhea. He has had recurrent episodes of high fever (temperatures of 40.0 to 40.6°C) over the past 6 years, beginning at 6 months of age, occasionally accompanied by abdominal pain. The frequency of fever has been increasing over the past 3 years, now occurring nearly every month. He is usually drowsy and sleepy during fever episodes, with chills before the onset of fevers. Recurrent fever episodes have been so debilitating that he has missed many school days, prompting an investigation for neglect. He has had many evaluations in the past, none of which have determined the cause of his fevers.His weight and height are at 95th percentile. His temperature is 40.3°C, heart rate is 81 beats/min, respiratory rate is 22 breaths/min, blood pressure is 110/58 mm Hg, and oxygen saturation is 98% in room air. He appears well but tired. Physical findings are unremarkable except for enlarged bilateral posterior cervical lymph nodes, with the largest being 1 cm.Laboratory results show a WBC count of 9.6×103/μL (9.6×109/L) (69% neutrophils, 19% lymphocytes, 10% monocytes, and 2% eosinophils). Liver function tests and urinalysis results are normal. The antinuclear antibody as well as Epstein-Barr virus and human immunodeficiency virus antibodies are negative. ESR is 24 mm/hr and C-reactive protein is 9.52 mg/dL. Additional laboratory evaluation reveals his diagnosis.Abdominal CT scan was obtained because of abdominal pain of long duration and showed thickening of the wall of the terminal ileum (Fig. 1). Endoscopy revealed hypertrophied mucosa at the greater curvature of the stomach, rectosigmoid junction, and distal splenic flexure. Biopsies from the esophagus, stomach, duodenum, jejunum, and terminal ileum yielded numerous eosinophils (15/high-power field) (Fig. 2). Gastric and duodenal biopsies were negative for Helicobacter pylori, and there was no evidence of cryptitis or abscess. Serial stool analyses for intestinal parasites performed before endoscopy were negative. The serum immunoglobulin E (IgE) concentration was normal, and radioimmune absorption studies for a panel of food allergens were negative. Evaluation for celiac disease (duodenal biopsy, antigliadin, and antitransglutaminase antibodies) was negative. Results of the inflammatory bowel disease (IBD) serology 7 panel were strongly indicative of Crohn disease (CD). The boy was treated with balsalazide, calcium, vitamin D, and prednisolone, which resulted in resolution of the symptoms, weight gain, and normalization of abnormal laboratory values.Hypocalcemia at this age has myriad causes, including hypovitaminosis D, malabsorption, hyperphosphatemia, hypomagnesemia, hypoparathyroidism, and poor diet as well as disorders of liver and kidney. Hypoalbuminemia, anemia, and gastrointestinal symptoms were clues suggesting malabsorption. This boy's clinical presentation and laboratory evaluation, including serologic markers, led to the diagnosis of CD.CD is an idiopathic chronic inflammatory disease of the bowel that can affect any part of the digestive tract, from mouth to anus, and has an annual incidence of approximately 3 to 5 per 100,000. Around 30% of patients are diagnosed before 20 years of age. As per the Montreal classification, patients may be classified by age, location (ileum, colon, ileocolic, or upper GI tract), and disease behavior (inflammatory, stricturing, or penetrating). (1) Fewer than one third of patients present with the triad of abdominal pain, diarrhea, and weight loss. Extraintestinal symptoms are more common in CD than in ulcerative colitis (UC) and account for approximately 20% of clinical manifestations. Oral aphthous ulcers, erythema nodosum, peripheral arthritis, nephrolithiasis, cholelithiasis, clubbing, and episcleritis are more frequent in CD. Perianal fistula, abscess, and skin tags suggest the diagnosis of CD.Perturbation in calcium homeostasis is a well-known complication of CD, and approximately one third of patients have hypovitaminosis D. Hypocalcemia is more prevalent in association with long-standing cases, winter season, dark skin complexion, upper GI involvement, high ESR, low body mass index, hypoalbuminemia, inadequate nutritional supplementation, and concomitant glucocorticoid therapy.Endoscopic hallmarks of CD are skip lesions, cobblestoning, aphthous ulcers, strictures, fistula, ulceration of ileocecal valves, and rectal sparing. These findings, however, occur in only 64% of cases. The histologic finding of noncaseating granulomas is diagnostic of CD, but these are seen in only 28% of cases. In pathologic specimens, transmural inflammation helps to discriminate CD from UC. In this patient, biopsy showed only eosinophilia and did not reveal the characteristic granulomas. IBD is characterized by an overproduction of eotaxin 1 (a chemokine responsible for recruitment of eosinophils in tissues). The degree of eosinophilia is inversely proportional to the prognosis. Gastrointestinal eosinophilia also can result from primary GI eosinophilia, hypereosinophilic syndrome, parasitic infestation, allergic disorders, gastroesophageal reflux, Helicobacter pylori infection, drug reactions, celiac disease, lupus erythematosus, malignancy, and organ transplantation.IBD 7 is a comprehensive serologic test that helps to identify IBD and differentiate between UC and CD. It includes seven tests, of which anti-Saccharomyces cerevisiae antibody, anti-OMPc (antibody to outer membrane protein), and anti-CBir1(antibody to flagellin) are the serologic markers for CD.Mild cases of CD are treated with aminosalicylates or enteric-coated budesonide. Aminosalicylates such as olsalazine, sulfasalazine, and balsalazide are prodrugs that have an active 5-ASA moiety. Budesonide is effective only in disease confined to the ileum and ascending colon. Corticosteroid enemas are used for treating CD that involves the distal colon. Severe disease necessitates therapy with prednisone. Those who have corticosteroid-dependent or refractory disease need thiopurines (azathioprine or 6-mercaptopurine). Thiopurine methyltransferase genotype or enzyme activity should be evaluated before beginning therapy with thiopurines because this status can affect response and toxicity. Methotrexate is used in patients who develop resistance or toxicity to azathioprine and 6-mercaptopurine.Infliximab (a monoclonal antibody to tumor necrosis factor) is used in patients who have suboptimal responses to conventional therapy. Adverse reactions include infusion reaction, reactivation of latent tuberculosis, opportunistic infections, demyelinating disease, development of autoantibodies, and T-cell lymphoma. Metronidazole or ciprofloxacin is used as initial therapy for perirectal fistulas. Nonhealing cases require thiopurines or infliximab. Surgery is indicated when there is perforation, stricture, intractable bleeding, abscess, or disease refractory to medical treatment. Nutritional rehabilitation and psychosocial therapy are important adjunctive treatments.CD is a chronic disorder that involves remissions and intermittent disease flares. Onset before 20 years of age is associated with a poorer prognosis. Because extensive and long-standing disease increases the risk for malignancy, screening is recommended for older patients.Additional laboratory test results included the following: serum cortisol at 10:20 pm was 1.1 μg/dL (30.3 nmol/L) (normal pm range, 2 to 10 μg/dL [55.2 to 275.9 nmol/L]), thyroid-stimulating hormone was 6.25 mIU/mL (normal range, 0.6 to 10.0 mIU/mL), and free thyroxine was 0.8 ng/dL (10.3 pmol/L) (normal range, 0.6 to 1.75 ng/dL [7.7 to 22.5 pmol/L]). Brain MRI revealed an ectopic posterior pituitary gland and pituitary gland hypoplasia, absence of the anterior portion of the septum pellucidum, and hypoplasia of the left optic nerve and optic chiasm. These findings are consistent with septo-optic dysplasia (SOD), also known as De Morsier syndrome.The patient was treated initially with hydrocortisone, and levothyroxine was added subsequently. Because of persistent hypoglycemia, growth hormone deficiency (GHD) was diagnosed clinically, and growth hormone treatment was instituted.SOD is a rare condition occurring in 1 in 10,000 live births. It is highly heterogeneous and defined loosely by the triad of optic nerve hypoplasia, midline neuroradiologic abnormalities (such as agenesis of the corpus callosum and absence of the septum pellucidum), and pituitary hypoplasia with associated hypopituitarism. Generally, two of the three conditions must be present for diagnosis. The disorder is equally prevalent in males and females. Most cases are sporadic, but familial cases have been described. For unknown reasons, cases occur more often in infants born to young mothers.Clinical features in infancy may include respiratory distress on the first postnatal day, metabolic acidosis, hypotonia, severe hypoglycemia, hypogenitalism, and midline CNS defects. As many as two of three patients develop endocrine deficits ranging from isolated GHD to panhypopituitarism; progressive loss of endocrine function may occur over time. Both cholestatic and noncholestatic jaundice have been associated with the condition. Hyperbilirubinemia resolves in most cases once hormonal replacement therapy is initiated. Neurologic deficits are common but highly variable, ranging from severe intellectual disability to mild focal deficits.Hypoglycemia and hypothermia (with or without hyperbilirubinemia) in the newborn period always should raise concern for sepsis, and a thorough evaluation and appropriate treatment should ensue.Causes of hypoglycemia in the newborn period include hyperinsulinemia (as occurs in infants born to mothers who have toxemia or gestational diabetes mellitus), limited glycogen stores (from prematurity, intrauterine growth restriction, starvation, and perinatal stress), increased glucose use (seen in hypothermia, polycythemia, and sepsis), endocrinopathies (such as adrenal insufficiency or GHD), decreased glycogenolysis, diminished gluconeogenesis, and inborn errors of metabolism.Evaluation for hypoglycemia should be performed when the patient is symptomatic (blood glucose <50 mg/dL [2.8 mmol/L]) and should include assessment of serum glucose and insulin, cortisol, growth hormone, lactic acid, free fatty acids, and beta-hydroxybutyrate as well as a complete metabolic panel that includes liver function tests. In addition, plasma concentrations of ammonia, an acyl-carnitine profile, and urine organic acids should be measured. The newborn screen results should be reviewed.At 2 weeks of age, any infant who has jaundice should be evaluated by measuring total serum bilirubin and conjugated bilirubin. Elevation of conjugated bilirubin in infancy is defined as a serum concentration greater than 1.0 mg/dL (17.1 μmol/L) if the total bilirubin is less than 5.0 mg/dL (85.5 μmol/L) or more than 20% of the total bilirubin if the total bilirubin is greater than 5.0 mg/dL (85.5 μmol/L).Although a large number of conditions are associated with conjugated hyperbilirubinemia, relatively few account for the majority of cases. Idiopathic neonatal hepatitis syndrome and biliary atresia account for 70% to 80% of cases, and alpha-1-antitrypsin deficiency accounts for another 5% to 15%. The initial step in evaluation should be to identify treatable disorders of neonatal hepatitis syndrome, such as sepsis, other neonatal infections (such as TORCH infections), hypothyroidism, panhypopituitarism, and inborn errors of metabolism (galactosemia). The next step is directed at evaluation of possible extrahepatic biliary atresia because surgical intervention within the first 2 postnatal months results in improved outcome in infants who have biliary atresia.Once the diagnosis of SOD is confirmed, appropriate treatment should be initiated. Urgent treatment of hypoglycemia may require intravenous dextrose. Therapy with hydrocortisone and growth hormone may be necessary for long-term maintenance of euglycemia. Thyroid hormone replacement must be instituted as soon as the diagnosis of thyroid hormone deficiency is established; long-term treatment with thyroid hormone, involving careful monitoring of concentrations and titration of dosage, offers the best outlook for physical growth and neurodevelopmental progress. Because treatment with thyroid hormone can precipitate adrenal crisis in patients who have untreated adrenal insufficiency, replacement of glucocorticoid must precede thyroid hormone treatment. Continued assessment and appropriate treatment of other hormonal deficiencies, such as diabetes insipidus and hypogonadism, is essential. Affected infants also need evaluation by specialists in ophthalmology, neurology, and childhood development.This patient was treated with thyroid hormone, hydrocortisone, and growth hormone. His hypoglycemia, hypothermia, and hyperbilirubinemia resolved, and the serum transaminase values normalized. His growth is being monitored, as are his developmental progress, visual function, and signs of possible diabetes insipidus and hypogonadism. The latter condition typically is not diagnosed until the expected time of pubertal development.The boy's evaluation showed serum of mg/dL (normal, to mg/dL to of mg/dL (normal, to mg/dL to and of mg/dL (normal, to mg/dL to His however, were at mg/dL (normal, 4 to mg/dL to a diagnosis of D syndrome was fever or human a of disease that result in recurrent episodes of usually by a in the that and These disorders typically are after have been are usually present with high with symptoms such as pain, abdominal pain, and usually resolve on resolution of which may to weeks without any medical fever is by the most common is an disorder by a in the fever on which the protein is in Affected patients usually present with and symptoms that to laboratory and evaluation and is a common complication of in fever syndrome is tumor necrosis fever which is also known as familial The of is with The occurs in the for the Affected patients usually present with for at 5 and up to 2 The fever typically is accompanied by and with pain, and abdominal was first in by in the (1) is characterized by recurrent temperatures up to accompanied by and common symptoms include abdominal pain, diarrhea, nausea, vomiting, and to of patients have during fever episodes, usually in the cervical the are and than two of patients the first of fever before first most common characteristic of is serum serum values may be normal until age 3 The of is in of or but the disorder can be in of other an and the is on in the who have have activity of an enzyme that acid, an of and It is that the in leads to increased of to increased inflammation and patients who have and develop patients who have develop this period from onset of disease to diagnosis is usually 10 years because the disease is not until the history reveals a of fever over time. It is however, to the condition than because can extensive evaluations and missed school for patients and for A to the condition may be that episodes are by and mild can be diagnosed when the patient presents with the previously symptoms and has an serum concentration mg/dL Because values can be normal in the if the patient presents with clinical features strongly of can be the patients usually have patients can present with serum Because patients have an to acid, acid can be in the This can be by the of acid to creatinine in this finding should not be used as a should be as evidence for the diagnosis. Currently, studies are concentrations in urine as another diagnostic for is no known therapy for and such as and have been with

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