Case 1 Presentation
A 3-year-old Caucasian girl is brought to the community clinic of a rural town because of cough and fever. She looks extremely pale, and a hemoglobin level by finger stick is 1.12 mmol/L (1.8 g/dL). There is no history of trauma, pica, hematemesis, hematochezia, melena, jaundice, or tea-colored urine. The only medication she has taken recently is ibuprofen. She is transferred to the pediatric ward of the regional hospital.
On physical examination, her weight is 10.9 kg, temperature is 39.2°C (102.6°F), pulse is 142 beats/min, and blood pressure is 117/62 mm Hg. She is alert and cooperative, but appears ill, is in mild respiratory distress, and is extremely pale, with no pink color in the nail beds. She has no jaundice or lymphadenopathy. She is breathing at 66 breaths/min with mild retractions; inspiratory and expiratory crackles are audible over the left lung base. An S3 gallop rhythm is noted. Her abdomen is slightly distended. The liver edge is palpable 2 to 3 cm below the costal margin, but the span is normal; the spleen is not palpable. There is mild pretibial edema. Her hemoglobin level is 0.87 mmol/L (1.4 g/dL), hematocrit is 0.054 (5.4%), platelet count is 242 × 109/L (242 × 103/mcL); and leukocyte count is 24 × 109/L (24 × 103/mcL), with 45% neutrophils, 31% band forms, 22% lymphocytes, and 2% metamyelocytes. The mean corpuscular volume (MCV) is 50.5 fL (normal, 82 to 98 fL). The blood smear, reviewed by the pathologist, does not show any blasts. Further evaluation, including detailed history and further laboratory assessment, reveals the causes of the anemia.
Case 2 Presentation
You are called by the nursery nurse to evaluate a 3-day-old infant who has fed poorly since shortly after birth and seems to be unusually “tight.” The girl was born to unrelated parents at term by breech delivery after an uneventful pregnancy. The tetanus immunization status of her mother is up-to-date, and there is no history of drug abuse. The family history is unremarkable, and her six older siblings are healthy. Birthweight was 3.2 kg, and her Apgar scores were 6 and 9 at 1 and 5 minutes, respectively; no resuscitation was required.
Physical examination reveals an irritable infant who has no dysmorphic features but whose sucking and swallowing are poor. There is generalized hypertonicity that is more pronounced when the baby is awake and disappears during sleep. The tendon reflexes are brisk, and the startle reflex is exaggerated. No other abnormalities are noted.
The results of multiple investigations, including blood gases, serum glucose, calcium, electrolytes, complete blood count, cerebrospinal fluid (CSF) studies, and urine toxicology screening for opiates, barbiturates, cocaine, and amphetamines, all are normal. Blood and CSF bacteriologic cultures remain negative. Cranial ultrasonography and electroencephalography (EEG) during the hypertonic episodes yield normal findings, as do nerve conduction velocity studies. Additional testing rules out gastroesophageal reflux. Electromyography shows an almost permanent muscular activity, even during rest, with occasional periods of electric quietness.
Case 3 Presentation
A 3 1/2-year old girl who has spastic quadriplegic cerebral palsy due to prematurity and birth asphyxia is admitted to the hospital because of increasing tachypnea and respiratory distress. Two months ago, her parents began to notice increasingly rapid breathing, use of her accessory muscles, weight loss, and changes in her fingertips. There is no history of fever, upper respiratory congestion, cough, aspiration events, foreign body ingestion, or contacts with ill people. She has not improved despite treatment with amoxicillin and clarithromycin.
The girl is fed exclusively by mouth and has no history of asthma or aspiration pneumonia. Intermittent constipation has been managed with prune juice, glycerine suppositories, and mineral oil.
On physical examination, the child appears chronically ill and undernourished. Her weight is well below the 3rd percentile, with no weight gain since age 18 months. She is afebrile. Respiratory examination shows tachypnea, intercostal retractions, decreased air entry into the lower lung fields, no audible crackles or wheezes, and digital clubbing.
Initial investigations reveal an oxygen saturation of 89° in room air, a chest radiograph showing bilateral airspace disease with relative sparing of the upper lobes, and normal hemoglobin level and white blood cell count.
She is managed with supplemental oxygen and intravenous penicillin. A radiologic feeding assessment shows no evidence of aspiration, and a sweat chloride level is in the normal range. The child fails to improve, and a further element of history leads to the diagnosis.
Case 1 Discussion
The dietary history revealed that since late infancy the patient, who is the youngest of four children, has continued to drink six 8-oz bottles of cow milk per day, with nearly no intake of solid foods. Her mother was diagnosed as having beta thalassemia trait during her first pregnancy after she was found to have a reduced hemoglobin level. The mother is of Irish and Native-American descent and is not aware of any Mediterranean or southeast Asian ancestry.
After a phone consultation with a pediatric hematologist, blood was obtained to measure lead, ferritin, and iron levels as well as total iron binding capacity (TIBC) and for hemoglobin electrophoresis. The patient then was transfused with packed red blood cells (RBCs). The rate of infusion was to be 20 mL/h over 10 hours. When the nurse pointed out that the 200-mL bag sent by the blood bank had to be given within 4 hours, the rate was increased reluctantly to 50 mL/h.
The patient initially looked better, with her color becoming slightly pink and her pulse decreasing to 120 beats/min. However, 1 hour later she developed pulmonary edema and frank heart failure due to volume overload. She was intubated, given furosemide, and transported to the university hospital for intensive care. Blood test results later showed severe iron deficiency anemia, as evidenced by a serum iron level of 1.08 mcmol/L (6 mcg/dL) (normal, 7.2 to 21.6 mcmol/L[ 40 to 120 mcg/dL]), ferritin of 4 ng/ml (normal, 10 to 300 ng/mL), TIBC of 59.61 mcmol/L (333 mcg/dL) (normal, 45.54 to 79.66 mcmol/L [260 to 445 mcg/dL]), lead level of 0.9 mcg/dL, and a hemoglobin pattern consistent with beta thalassemia trait.
Anemia may be due to blood loss, inadequate production of RBCs, or excessive destruction of RBCs. One common cause remains iron deficiency, although the incidence of iron deficiency in the United States has declined because of improved dietary practices. Other important causes to consider are the hemoglobinopathies, hemolysis, and nutritional deficiencies of substances such as vitamin B12 or folate. Anemia is associated with chronic diseases, renal disease, malignancy, and lead poisoning. Transient erythroblastopenia of childhood can produce a severe normochromic, normocytic anemia during infancy.
The differential diagnosis of anemia usually can be narrowed after a thorough history, physical examination, and a few simple laboratory tests. The history should include questions related to the present illness, blood loss, diet, pica, intake of medications, past history of anemia, and family history of anemia, splenectomy, cholecystectomy, or blood transfusion. The physical examination may show pallor, jaundice, lymphadenopathy, signs of heart failure, or specific signs associated with one particular type of anemia. RBC indices, including the RBC count, MCV, and RBC distribution width (RDW) are useful in classifying the type of anemia, as is a reticulocyte count. It is essential to examine a peripheral blood smear because specific features of the blood cells may point to the diagnosis, including designation of the cells as microcytic, normocytic, or macrocytic. Depending on the elements of history and physical examination, a stool test for occult blood, urinalysis, or measurement of levels of bilirubin, blood urea nitrogen, or creatinine may be added to the initial evaluation.
The presence of iron deficiency in any child or adult always requires an explanation for the deficiency. Iron is transported actively across the placenta at a gradient that favors the fetus. Consequently, newborn iron stores are altered only when maternal iron deficiency is severe. Approximately 85% of iron stores in the newborn are in RBC hemoglobin. Infants have a dietary requirement for iron because they are growing rapidly and expanding their RBC mass. The peak incidence of dietary iron deficiency in infancy occurs between the ages of 6 months and 2 years. It rarely is encountered in term infants younger than 4 months of age unless the baby has lost iron through blood loss. Because of their lower iron stores and RBC mass at the time of birth and their more rapid growth, preterm infants are at greater risk than term infants for developing dietary iron deficiency. Dietary iron deficiency also can develop in adolescents who are experiencing growth spurts, particularly in adolescent girls who also may be losing iron from menstrual bleeding.
The dietary history in a patient who has iron deficiency anemia due to an inadequate diet usually reveals the consumption of large amounts of cow milk and small amounts of foods rich in iron. A heat-labile protein in cow milk can cause occult, chronic intestinal blood loss in some children. This reaction to the heat-labile protein is not related to cow milk protein intolerance or to lactase deficiency. The loss of blood in the stools can be prevented by using heated or evaporated milk and restricting the intake of milk. Current recommendations specify that a 3-year-old child should drink 16 to 20 oz of milk each day. Clinicians also must encourage the intake of iron-rich foods.
In children and adults who are not growing rapidly, iron deficiency usually develops because of blood loss. Hemolysis is a rare cause. Iron deficiency does not occur from hemolysis unless the hemolysis is intravascular, which allows for loss of iron in the urine. For children who are not actively growing and for adults, the diagnosis of iron deficiency should prompt further investigations into the cause of bleeding. Children and adults who have iron deficiency from inadequate diet or from blood loss may experience pica, which is defined as the repetitive eating of nonnutritious substances. Examples of pica include eating dirt, paint peelings, paper, excessive ice cubes, or laundry starch, or licking dirt from under window ledges or window blinds. The occurrence of pica in a patient who has a severe microcytic anemia with an elevated RDW is strongly suggestive of iron deficiency. In such situations, it would be appropriate to institute iron therapy without requiring additional laboratory confirmation of iron deficiency. Other laboratory findings that confirm the diagnosis of iron deficiency include low serum ferritin and iron levels in conjunction with an elevated iron binding capacity. A decrease in serum iron also occurs in patients who have chronic infections, malignancy, or inflammatory conditions; an isolated decrease in serum iron should not be used to diagnose iron deficiency. Patients who have iron deficiency also have elevations in free erythrocyte protoporphyrin.
Iron deficiency anemia usually is treated with oral ferrous sulfate (3 to 6 mg/kg per day of elemental iron). The iron is absorbed better if given between meals and along with a drink containing vitamin C. It is appropriate to have the patient take iron for at least 1 to 2 months after the hemoglobin level has been corrected to fill iron storage sites.
Blood transfusion is necessary only in very severe cases, when the hemoglobin level is below 2.48 mmol/L (4 g/dL). Other clinical factors, such as the presence of cardiorespiratory distress, play a role in the decision to transfuse the patient. Packed RBCs are given slowly or in increments separated by several hours, and the amount per increment should not exceed 3 mL/kg per hour. A rapid transfusion may precipitate frank heart failure due to hypervolemia. One regimen consists of the infusion of 5 mL/kg of RBCs over 2 to 3 hours, followed by a waiting period of 1 hour and the infusion of an additional 5 mL/kg over 2 to 3 hours. Complete correction of the hemoglobin level by transfusion is not necessary. Administration of furosemide before the slow transfusion may help avoid heart failure. A partial exchange transfusion should be considered if frank heart failure already is present.
This patient received approximately 7 mL/kg of packed RBCs and developed frank heart failure. Her hemoglobin level rose to 3.53 mmol/L (5.7 g/dL). During her stay in the intensive care unit, she developed other complications. She suffered two pneumothoraces due to mechanical ventilation and required placement of bilateral chest tubes. She developed Staphylococcus aureus bacteremia, associated with a central intravenous line, which also was responsible for thrombosis of the right femoral and iliac veins. She eventually recovered without sequelae. Four months later, her hemoglobin level was 6.14 mmol/L (9.9 g/dL). One of her siblings also was found to have beta thalassemia trait.
A review of the child’s previous medical records showed that she had been hospitalized by another physician for gastroenteritis and dehydration at 2 years of age. At that time, her hemoglobin level was 5.58 mmol/L (9 g/dL) and MCV was 47.3 fL. Hemoglobin electrophoresis revealed 5.1% hemoglobin A2 (normal, 1.5% to 4.0%) and 4.5% hemoglobin F (normal, 0 to 2%), a pattern consistent with beta thalassemia trait. Unfortunately, these results were not available until well after the child was discharged, and the parents were not informed because of a communication problem.
LESSONS FOR THE CLINICIAN
This case reminds the clinician that a constellation of symptoms and signs may be due to more than one disorder. The severity of anemia in this patient, which was due primarily to iron deficiency, may have been exacerbated by the pre-existing beta thalassemia trait. Another lesson is the demonstration of the extent to which a child’s hemoglobin level may drop without catastrophic results, as long as the decline occurs slowly. The case also induces the clinician to reflect on “systems errors,” iatrogenic complications, communication with parents, and prevention of nutritional deficiencies. As a result of this child’s experience, the blood bank of the regional hospital now prepares smaller quantities of blood for pediatric patients. (Habib Rathle, MD, Yuma, AZ, and John Hutter, MD, University of Arizona Health Sciences Center, Tucson, AZ)
Case 2 Discussion
The association of generalized muscular rigidity, hypertonia in flexion, and an exaggerated startle response, in the absence of other identified disorders, in this infant led to the diagnosis of hyperexplexia, and oral diazepam was prescribed at a dose of 0.5 mg every 8 hours. Her feeding pattern improved quickly, and her muscle tone decreased progressively over the next few months. At 2 weeks of age, electromyography was repeated and revealed normal patterns. The child’s developmental milestones and the results of the neurologic examination were entirely normal at 1 year of age.
Hyperexplexia, known also as hyperekplexia or stiff-baby syndrome, is a rare autosomal dominant neurologic disorder. It manifests at birth with generalized muscular rigidity, hypertonia in flexion with closed fists, and an exaggerated startle response. These signs typically are heightened by the slightest stimulus, including nose tapping, and disappear with sleep. Hypertonia diminishes during the first 2 to 3 years of life. Motor retardation often is present without intellectual deficit. There is an increased risk of congenital dislocation of the hips and also of umbilical, inguinal, and hiatal hernia (which can be a risk factor for aspiration) due to increased abdominal pressure. Sudden death has occurred in patients who have hyperexplexia and may be related to complete heart block and apnea during seizure-like episodes. Dramatic improvement follows the use of diazepam or clonazepam.
Findings on EEG, nerve conduction velocity studies, and evoked potential testing (somatosensory, brainstem, and cortical) are normal. Electromyography shows a pattern of sustained muscular activity with intermittent periods of electrical quiet. The sustained muscular activity disappears with benzodiazepine treatment.
PATHOGENESIS AND GENETICS
Current pathogenetic hypotheses for hyperexplexia include the presence of abnormalities in the brain stem inhibitory system and neuromediator or receptor dysfunction. The physiology is believed to involve increased excitability of reticular neurons in the brainstem (and possibly in the spinal cord), leading to exaggerated primitive withdrawal reflexes. Hyperexplexia is the first human disease shown to result from mutations within a neurotransmitter gene. CSF gamma-aminobutyric acid (GABA) levels were reported to be low in affected patients, and because clonazepam acts through the GABA type-A receptors, a genetic defect in the GABA neurotransmitter receptor is thought to be the cause of this disorder.
The condition is linked to a DNA marker on the long arm of chromosome 5 and is associated with point mutations at the channel-forming segment M2 of the glycine receptor alpha-1 subunit GLRA1. Both recessive and dominant mutations in GLRA1 have been found in affected individuals. Mutation analysis of GLRA1 also is likely to be useful as an aid to genetic counseling and in the diagnostic evaluation of neonatal hypertonia.
The differential diagnosis in a newborn who has increased muscle tone is extensive. Tonic seizures may occur after birth asphyxia or meningitis or in patients who have metabolic abnormalities, but they do not increase with stimuli or decrease with sleep, and findings on the EEG usually are diagnostic. Neonatal drug withdrawal syndrome usually occurs 24 to 72 hours after birth and may be suspected by maternal behavior or drug history as well as by the presence of other signs in the neonate, such as diaphoresis, high-pitched cry, sneezing, yawning, ravenous appetite, vomiting, diarrhea, and poor temperature regulation. Drug withdrawal is confirmed by a urine toxicology screen.
Neonatal tetanus is very rare and may occur in infants of incompletely immunized mothers. It usually is associated with an infected umbilical stump, and symptoms do not occur in the first week of life. Opisthotonos and trismus may be present, and the dorsal and facial muscles are affected more frequently than the limbs. The symptoms do not disappear during sleep. Congenital arthrogryposis may result from neuromuscular pathology and may be accompanied by polyhydramnios. In these patients, the limbs are frozen in a fixed deformity (flexion or extension), and this positioning is not influenced by stimuli or sleep. Sandifer syndrome is associated with gastroesophageal reflux and manifests as torticollis and arching of the body.
Patients who have hyperexplexia may have apneic spells. Apnea is very unusual in term infants in the absence of birth asphyxia, seizures, central nervous system hemorrhage or malformation, or sepsis. Apparent life-threatening events or near-sudden infant death syndrome occur after the neonatal period and may be associated with apnea and cardiorespiratory arrest, but startle reactions and muscular rigidity do not occur.
Data regarding drug therapy is scanty, anecdotal, and not derived from randomized double-blind studies. Benzodiazepines, primarily clonazepam, are the drugs used most often, with clinicians initiating therapy at dosages that can control severe symptoms, then titrating the dose to obtain the desired clinical response. There are no formal guidelines for the duration of therapy; most authors begin to taper the dose as soon as clinical improvement has been achieved, although therapy up to 3 years of age has been reported. Some authors recommend a clonazepam dose of 0.05 to 0.1 mg/kg per day.
LESSONS FOR THE CLINICIAN
Hyperexplexia should be considered in the evaluation of neonates and infants who have suspected seizures, apnea, aspiration pneumonia, hyperexcitability, and near-miss sudden infant death syndrome. By diagnosing this condition correctly, the clinician may spare the patient unnecessary investigation and allow him or her to receive specific treatment and subsequent supervision. Families need to be informed of the genetic nature of the disorder, which may recur in future pregnancies. (Hassib Narchi, MD, Saudi Aramco Al-Hasa Health Center, Mubarraz, Saudi Arabia)
Case 3 Discussion
The radiographic findings were believed to be consistent with aspiration, and on further questioning, the child’s parents said that periodically they administered mineral oil by syringe into the back of her throat, often prompting cough. Results of computed tomographic (CT) scan suggested the presence of fat on T1-weighted images. The clinical scenario, combined with the CT findings, was believed to be diagnostic of a lipoid pneumonia caused by mineral oil aspiration. Antibiotics were discontinued, and the respiratory symptoms gradually improved. The child remains dependent on home oxygen therapy 7 months after her initial presentation, and a gastrostomy tube has been inserted to maximize her nutritional status.
PATHOGENESIS AND EVALUATION
Mineral oil is a nonvolatile hydrocarbon compound used frequently as a laxative in the management of constipation. Aspiration of the compound into the lungs is a recognized rare, but potentially life-threatening, complication. Deposition of mineral oil in the lungs leads to an intense foreign body reaction that culminates in proliferative fibrosis that is maximal in the dependent portion of the lungs. The clinical and radiographic findings are nonspecific, and the diagnosis depends on suspicion when encountering the clinical situation. A conclusive diagnosis has relied in the past on the finding of lipid-laden macrophages obtained by bronchiolar lavage or open-lung biopsy, but CT findings have been found to be specific and diagnostic.
Treatment is primarily supportive, with antibiotic administration reserved for patients who develop secondary infections. Several case reports have described beneficial effects from the use of steroids, but the largest published series of patients having lipoid pneumonia who were randomized prospectively to steroid therapy or placebo found no benefit from the use of steroids. Patients who are severely affected can acquire a long-term oxygen requirement. Death can result from this condition.
Acute aspiration pneumonias and chronic microaspiration of food particles, gastric contents, and oral secretions are common causes of morbidity and ultimately mortality in children who have severe neurologic impairment. Management of those who have potential swallowing dysfunction and are at risk of aspiration is enhanced by the involvement of occupational therapists, who can perform clinical and radiologic feeding assessments. Children in whom oral feedings are unsafe often are managed with gastrostomy tube alimentation. Gastroesophageal reflux disease is a frequent comorbid condition that is treated with histamine2 antagonists, prokinetic agents, and surgical fundoplication. Clinicians should consider evaluating patients who have severe neurologic impairment for reflux.
LESSONS FOR THE CLINICIAN
Mineral oil is a common treatment for chronic constipation and generally is well-tolerated, causing infrequent systemic side effects. Unintentional aspiration is an uncommon but serious complication associated with significant morbidity and mortality. Alternative treatments for constipation in children who are at risk of aspiration include lactulose, which has a wide margin of safety, docusate, milk of magnesia, and suppositories. Mineral oil should not be used in any child who has swallowing difficulty. (Michael Weinstein, MD, The Hospital for Sick Children, Toronto, ON, Canada)
- Copyright © 2000 by the American Academy of Pediatrics