Index of Suspicion

Abstract

An 11-year-old boy presents to the emergency department with a 1-week history of frequent episodes of nonbloody, nonbilious emesis associated with diarrhea and abdominal cramping. He has urgency and fecal incontinence. He has been afebrile and denies any rashes, joint pain, sick contacts, headaches, or other symptoms. On further questioning, his mother reveals that he has had 2 similar episodes of abdominal distension and diarrhea during the past 6 to 7 years. Between these episodes, she states that he normally has nonbloody, hard stools accompanied by straining and chronic abdominal pain and pain with defecation. When asked specifically, his mother does not remember when he passed his first stool after he was born.On physical examination, his temperature is 37.6°C, pulse is 100 beats per minute, respiratory rate is 16 breaths per minute, blood pressure is 113/62 mm Hg, oxygen saturation is 100% on room air, height is 63 inches (95%), and weight is 36.7 kg (25%). He has abdominal distention and diffuse abdominal tenderness with voluntary guarding. There is palpable stool in the left quadrant. There is no perianal erythema or skin tag, and rectal examination reveals a low anal tone.A CT scan of the abdomen (Figure 1) reveals a markedly distended rectosigmoid colon with circumferential, confluent, and contiguous mural thickening. Basic metabolic profile, CBC, and urinalysis results are unremarkable, but the C-reactive protein level is elevated at 131 mg/L (1248 nmol/L). Because of the concern for enterocolitis, he is empirically given broad-spectrum intravenous antibiotics and transferred to a children’s hospital for further evaluation.A 4-year-old boy presents for evaluation of intermittent fevers of 4 weeks’ duration after 2 separate antibiotic courses prescribed for acute otitis media. He has experienced clear rhinorrhea and cough intermittently during the febrile period and has decreased activity and food intake in the last 3 days. He was born at term via an uncomplicated vaginal delivery. He has a history of recurrent episodes of otitis media, requiring tympanostomy tube placement at age 2 years. His immunizations are up-to-date.Physical examination reveals a pale, thin, white boy. His weight is between the third and 10th percentiles, and height is at the 50th percentile. Oropharyngeal examination reveals scant tonsillar tissue with no erythema, exudate, or petechiae. He has decreased breath sounds in the right lower lung field, and crackles are appreciated in the same area. Cervical, epitrochlear, axillary lymph nodes are small and difficult to palpate.Laboratory studies reveal the following: WBC, 26.3 × 103/μL (26.3 × 109/L) with 90% neutrophils and 6% lymphocytes; Hct, 28.3%; platelets, 520 × 103/μL (520 × 109/L); and ESR, 38 mm/hour. Chest radiograph reveals a right lower and middle lobe pneumonia with evidence of effusion, which is confirmed by chest CT (Figure 2).The patient is transferred to a pediatric inpatient ward for intravenous antibiotic therapy and video-assisted thoracoscopic surgery for drainage of the pleural fluid. In preparation for the surgery, the patient’s blood is typed and crossed-matched, which reveals an O negative blood type and absent isohemagglutinins. On the basis of these findings, additional laboratory evaluation is ordered and confirms the diagnosis.A 15-year-old boy presents with a 1-year history of progressively increasing “lumps” in his breasts and a 3-month history of spontaneous milky discharge from both nipples. He reports a low energy level despite sleeping 14 hours per night. He is in a relationship and noticed a decrease in libido in the past few months. His appetite is normal, and he is surprised by a lack of muscle gain despite regular exercise. He has a 1½-year history of headaches, worse after school, without associated visual symptoms or vomiting. He does not have dry skin, cold intolerance, or constipation. His medical history is unremarkable. He began puberty and adrenarche spontaneously at age 11 years. He is not taking any medications.Physical examination reveals a well-appearing boy. His weight is at the 50th percentile, and his height is at the 25th percentile. His blood pressure and heart rate are within normal limits for age. He has gynecomastia bilaterally, and galactorrhea is not elicited during the examination. His thyroid gland is not enlarged. His testes are 25 mL bilaterally (reference range, Tanner V testes >20 mL), and he has Tanner stage V pubic hair. The results of his neurologic examination, including visual field testing, are normal.Normal laboratory findings include serum values of electrolytes, creatinine, urea, follicular stimulating hormone, luteinizing hormone, testosterone, thyroid-stimulating hormone, and free thyroxine. Two additional tests reveal the diagnosis and the cause of his gynecomastia and galactorrhea.At the children’s hospital, antibiotic treatment was continued and serial abdominal examinations performed. In addition, the patient also had a bowel cleanout with rectal irrigations and polyethylene glycol solution via nasogastric tube and was given an oral polyethylene glycol solution. The result of a rectal swab test for gonorrhea and chlamydia taken to evaluate for possible abuse was negative.Results of extensive laboratory evaluation, including stool for Clostridium difficile toxin and rotavirus antigen, as well as blood, stool, and urine cultures, were negative. His C-reactive protein level continued to remain elevated.After the bowel cleanout was complete, a full-thickness rectal biopsy was performed. The biopsy specimen was notable for a lack of ganglion cells in the submucosa and hypertrophied nerve fibers, confirming a diagnosis of Hirschsprung disease (HD) as a cause of his chronic constipation.HD or congenital aganglionic megacolon is caused by the incomplete craniocaudal migration of neural crest cells during fetal intestinal development, resulting in an absence of ganglion cells in the distal colon. Normally, the intestine is innervated by several neuronal plexi, including submucosal (Meissner), intermuscular (Auerbach), and a small mucosal plexus. There is also extrinsic cholinergic (excitatory) and adrenergic (inhibitory) innervation. In patients who have HD, there is a marked increase in extrinsic intestinal innervation; the cholinergic system predominates over the adrenergic, which leads to an increase in resting smooth muscle tone. Thus, the aganglionic segment of bowel fails to relax, resulting in a functional obstruction. Approximately two-thirds of children with HD will have an aganglionic segment that involves the distal rectosigmoid colon.In the United States, HD occurs in approximately 1 per 5400 to 7200 newborns, and approximately 20% of these infants will have one or more associated anomalies that involve the neurologic, cardiovascular, urologic, or gastrointestinal system. The typical presentation is in the newborn period; infants may have bilious emesis, abdominal distension, and delay in passage of meconium for greater than 48 hours. Similar to our case, older children may present with symptoms of failure to thrive, chronic constipation, and intermittent abdominal distension. In newborns, the rectal tone is usually normal or increased; however, in older children, it can be diminished or absent. In general, low anal tone is unusual in HD; the resting anorectal tone is generally normal to higher than normal and characteristically fails to demonstrate relaxation with distention.Another important clinical presentation is enterocolitis. In the setting of HD, this is a potentially life-threatening illness with rapid onset that consists of fever, vomiting, foul-smelling and often explosive diarrhea, and abdominal distension. The pathology of enterocolitis is thought to be related to stasis and bacterial overgrowth. HD-related enterocolitis must be treated aggressively with resuscitation, intravenous antibiotics, rectal irrigations, and occasionally diverting colostomy.The gold standard for diagnosis of aganglionosis is rectal biopsy, and the definitive method for obtaining tissue is to perform a full-thickness rectal biopsy. Suction rectal biopsy may also be used to obtain tissue in newborns because it can easily be performed at the bedside. Absence of ganglion cells establishes the diagnosis of HD.Diagnostic adjuncts include contrast enema, which may demonstrate a visible transition zone; this represents the change from the distal aganglionic segment to the proximal dilated normal colon. Localization of the transition zone may also be useful in identifying the estimated length of the aganglionic segment. Another useful study is anorectal manometry. A normal study would demonstrate relaxation of the internal anal sphincter with rectal distention, whereas lack of relaxation of the internal anal sphincter with distension is suggestive of HD.Surgery is the mainstay management for HD. Surgical procedures include resection of the aganglionic segment and creating an anastomosis of the normal bowel close to the anus while preserving sphincter function. Traditionally, patients require a colostomy to allow the dilated bowel to decompress. The definitive repair would then be performed later. More recently, many surgeons perform operative correction of HD in a single stage. There are several effective operative techniques used for treating HD, all of which rely on approximating normally innervated intestine within 1 cm of the anus. However, laparoscopic-assisted and transanal pull-through procedures that use endorectal dissection are being performed more frequently. Results appear to be equivalent to traditional pull-through procedures, with earlier resumption of full feeds, less pain, shorter hospitalization, and less scarring. Most patients do well after operative correction. Postoperative complications of any of these procedures include internal sphincter dysfunction, fecal incontinence, constipation, and enterocolitis.Because of the extent of the dilatation of the proximal sigmoid colon and the significant mural wall thickening, our patient had an ileostomy performed to allow his dilated bowel to decompress. He will have a laparoscopic-assisted Swenson procedure at a later date.An immunoglobulin panel revealed undetectable levels of serum IgG, IgA, and IgM. Flow cytometry revealed a complete absence of CD19+ B cells. Genetic analysis revealed a hemizygous mutation of the Bruton tyrosine kinase (BTK) gene, confirming a diagnosis of X-linked agammaglobulinemia.Our patient’s bacterial pneumonia and recurrent episodes of otitis media are consistent with the types of infections seen in patients who have humoral immunodeficiencies. This patient’s complete lack of detectable serum immunoglobulin narrows the differential significantly. Immunodeficiencies with undetectable immunoglobulins include X-linked agammaglobulinemia (BTK gene); autosomal recessive agammaglobulinemia, which includes μ-chain, λ5/14.1 (surrogate light chain), Igα, and the B-cell linker (BLNK) gene mutations; and numerous forms of severe combined immunodeficiency (adenosine deaminase, recombinase activating gene 1 or 2, Artemis, or ligase-4 gene deficiencies).Bruton or X-linked agammaglobulinemia (XLA) is named after Colonel Ogden Bruton, a US Army pediatrician who described the first recognized human host defect in 1952. Loss-of-function mutations of the X chromosome’s BTK gene results in arrested development of B cells at the pro-B-cell stage, a total or near-total loss of mature B cells, and panhypogammaglobulinemia. Transplacental transfer of maternal IgG antibodies protects the affected patients for the first several months of life. Patients who have XLA lack secretory IgA from the time of birth and may manifest in the first 6 months with an increased incidence of mucous membrane infections. Approximately one-third of patients affected by XLA have de novo or spontaneous mutations with no family history of the disorder.Recurrent infections, particularly involving the upper and lower respiratory tract, such as otitis media, sinusitis, and pneumonia, are common in XLA patients. These infections are commonly caused by encapsulated organisms, such as pneumococci and Haemophilus influenza. They may also experience infections with meningococci, staphylococci, and Pseudomonas spp. Growth and development are generally within normal limits unless they develop chronic or persistent enteric or pulmonary infections. Viral infections usually do not cause significant morbidity in these patients, except for hepatitis and enterovirus infections, which can cause viremia and death.Although patients are often described as having absent tonsils and lymphoid tissue, a more appropriate description is scant tonsillar tissue and peripheral lymph nodes. The decrease but not absence of lymphatic tissue is due to an absence of B-cell–rich germinal centers and not a complete absence of lymphatic tissue.Although most patients who have XLA begin to experience infections by age 1 year, with increasing access to broad-spectrum antibiotics and good hygiene, XLA is not diagnosed in many patients until they reach preschool or even school age. Several large case series have shown that the mean age of diagnosis for sporadic XLA is between 35 and 58 months. Because increasing numbers of BTK gene mutations are being identified, a broader spectrum of clinical manifestations of XLA is being recognized than in the past.If a humoral immunodeficiency is suspected, a CBC and a serum immunoglobulin panel (serum IgG, IgA, and IgM) need to be checked. In patients who have XLA, lymphocyte counts may be low because of the absence of B cells. In most patients who have XLA IgG, IgA, and IgM are severely depressed or absent. Isohemagglutinins, naturally occurring IgM antibodies to the polysaccharide antigens that define ABO blood type, are produced during the first year of life. Therefore, in patients who are not AB blood type, these antibodies are a useful measurement of B-cell function. Immunophenotyping in patients who have XLA demonstrates absence or low numbers of CD19+ B cells. Finally, gene mutation analysis should be performed to identify specific mutations within the BTK gene and to differentiate XLA from other less common forms of agammaglobulinemia. Genetic study is also helpful for genetic counseling.The mainstay of therapy for patients who have XLA is replacement of immunoglobulins delivered by intravenous or subcutaneous route. The overall prognosis of patients who have XLA is good if replacement therapy is instituted early. Patients who do not have bronchiectasis at the time therapy is initiated are generally treated with immunoglobulin at the dose of 400 to 600 mg/kg every 3 to 4 weeks. Despite this therapy, which generally prevents systemic infections, patients who have XLA may develop severe and persistent enteroviral infections and sinopulmonary infections because no effective means currently exists for replacing secretory IgA. Treatment with long-term antibiotic prophylaxis is often recommended to prevent pansinusitis or bronchiectasis. Patients who have XLA should continue to receive all routine vaccinations, including MMR and varicella vaccines. Live vaccines, such as oral polio, live attenuated flu vaccines, BCG, oral typhoid, and yellow fever, are contraindicated in these patients because of low incidence of these infections in the United States or the availability of killed versions of the vaccines.Our patient began replacement therapy while admitted for treatment of his pneumonia and empyema. He was also prescribed trimethoprim-sulfamethoxazole prophylaxis for sinupulmonary infections. Since discharge, he has done extremely well, with no subsequent infections. His growth has also improved, gaining almost 10% of his body weight in the first 3 months of therapy.Serum prolactin was 307 μg/L (reference range, <18 μg/L). MRI of the head showed a 0.7 × 0.6 × 0.5-cm lesion in the left side of the sella, consistent with a pituitary adenoma. He was diagnosed as having a prolactinoma, and cabergoline was prescribed at 0.25 mg orally biweekly. After 2½ months of treatment, his prolactin level was 24.1 μg/L.Prolactin is a hormone produced by lactotrophs in the anterior pituitary gland that stimulates milk production after childbirth. Prolactin secretion is under tonic inhibitory control by hypothalamic dopamine and is stimulated by estrogens, suckling, and thyrotropin-releasing hormone. Prolactinomas consist of lactotrophs that secrete prolactin. They represent 50% of all pituitary adenomas in children and adolescents, which represent 2% of all intracranial tumors. They are typically benign and are classified as microadenomas (<1 cm in diameter) or macroadenomas (>1 cm in diameter). They are more common in girls and typically present around the time of puberty, although they are most frequently seen in the adult population. Macroprolactinomas are more frequent in boys and are thought to be due to differences in tumor biology between the sexes.The clinical features of prolactinoma result from hyperprolactinemia. Increased prolactin stimulates milk production. It also has effects on gonadal function by inhibiting pulsatile gonadotropin-releasing hormone secretion and by a direct inhibitory effect on testicular and ovarian function. Large tumors can compress other pituitary cells or the hypothalamic-pituitary stalk. Neurologic symptoms, including headache and visual field defects, can occur secondary to mass effect.Girls typically present with delayed puberty, primary and secondary amenorrhea, and galactorrhea. Boys may present with delayed puberty, gynecomastia, and galactorrhea. They can have decreased energy, decreased libido, and impotence. Growth failure has been inconsistently reported in children with prolactinoma. Adolescents with prolactinoma have been found to have reduced bone mineral density. Neuro-ophthalmologic signs are more often seen in boys because of a higher prevalence of macroprolactinomas.Other potential causes of hyperprolactinemia are physiologic elevations, such as in pregnancy; conditions that interfere with hypothalamic dopamine production or compress the pituitary stalk, such as CNS tumors, head trauma, or surgery; use of dopamine receptor antagonists, such as risperidone and metoclopramide; renal or hepatic failure due to reduced prolactin clearance; primary hypothyroidism; neurogenic stimulation from a chest wall injury; or idiopathic hyperprolactinemia.The history should focus on other possible causes of elevated prolactin, such as pregnancy, medications, a history of renal or hepatic disease, and use of illicit drugs, such as marijuana. The patient should be asked about headache, visual symptoms, and symptoms of hypothyroidism. The physical examination should include visual field testing and looking for signs of hypogonadism and hypothy-roidism.The diagnosis of prolactinoma requires laboratory results of sustained hyperprolactinemia and imaging evidence of pituitary adenoma. Thyroid, renal, and hepatic function should be checked. Prolactin levels can be falsely elevated in the presence of macroprolactin, a complex of prolactin and an IgG antibody that has a reduced rate of clearance and reduced bioactivity. The presence of macroprolactin should be confirmed by polyethylene glycol precipitation, particularly in a patient with a moderately elevated prolactin level and less typical symptoms. After ruling out other possible causes of an elevated prolactin level, an MRI of the head with contrast should be performed. If a macroadenoma is found and the prolactin level is only mildly elevated, the assay should be repeated and diluted to look for a hook effect, which occurs when a very high serum prolactin level interferes with the assay. If a lesion is found on MRI, the levels of the remaining pituitary hormones should be evaluated.The primary therapy for prolactinoma is medical. Microadenomas do not always require treatment if the patient is asymptomatic, whereas macroadenomas should always be treated. Other indications for treatment include an enlarging microadenoma, infertility, bothersome galactorrhea, gynecomastia, testosterone deficiency, oligomenorrhea or amenorrhea.Treatment consists of dopamine receptor agonists that inhibit prolactin synthesis. In patients with microadenomas and amenorrhea where fertility is not a concern, treatment options are dopamine agonists or oral contraceptives. The recommended dopamine agonist is cabergoline as it has been shown to be more effective than other dopamine agonists in normalizing prolactin levels and decreasing the size of the tumor. An association with cabergoline and the development of valvular heart disease has been reported in patients who have Parkinson disease and are taking at least 3 mg of cabergoline daily, but this has not been shown in patients using low doses of cabergoline for treatment of hyperprolactinemia.The goals of therapy are to restore normal pubertal development, to decrease tumor mass, and to achieve an adequate peak bone mass. Guidelines recommend treatment with a dopamine agonist for at least 2 years. If prolactin levels are normal after 2 years of treatment and the tumor is no longer visible on MRI, a trial of tapering and possibly stopping the medication can be started. Little is known about the recurrence rates in children; however, recurrence is known to be high in adults, and therefore pediatric patients require ongoing, close follow-up.In the case of symptomatic patients where, despite maximal medical management, the tumor size fails to decrease or prolactin levels remain high, transphenoidal surgery is recommended.