Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 15-4

Nine-Day-Old Boy



A 9-day-old term boy was transferred from a local community hospital for further evaluation and management of sepsis and hyperbilirubinemia.

The infant had been discharged home from the well-baby nursery on the fourth day of life with a bilirubin of 16.7 mg/dL. A bilirubin level 2 days later was 19.4 mg/dL and he was admitted for phototherapy. Within 24 hours of admission he developed emesis and temperature instability. A blood culture and lumbar puncture were performed and ampicillin and gentamicin were started. Additional bilirubin measurements revealed the direct fraction to be 5.2 mg/dL. An ultrasound, performed to assess hepatomegaly, revealed a nondilated biliary system, small gallbladder, and diffuse hepatic enlargement. A nuclear medicine liver scan showed normal bile excretion.

The baby continued to receive breastmilk feedings (with nasogastric tube supplementation required because of poor oral intake) until he experienced blood-tinged emesis. Coagulation studies around this time revealed the PT and PTT to be more than 50 seconds and more than 200 seconds, respectively, for which vitamin K and a dose of fresh frozen plasma were administered. By report, the baby’s abdomen was soft and his stool quantity and quality were unremarkable. Transfer to a tertiary care center was arranged.


The infant was born to a 27-year-old G1P0 mother with unremarkable prenatal labs. Delivery was via cesarean section at 37 weeks because of breech presentation. The baby’s birth weight was 3.04 kg. He was discharged with his mother on the fourth day of life and was breastfeeding every 3 hours.


T 36.4°C; HR 140 bpm; RR 60/min; BP 83/50 mmHg; Weight 2.7 kg (5th-10th percentile)

Physical examination revealed a 9-day-old term boy who was listless but arousable. His skin demonstrated a yellow-green jaundice but no pete-chiae, rash, or bruising. He was nondysmorphic and normocephalic with an open, flat fontanelle; his pupils were equal, round, and reactive with red reflexes present bilaterally; mucous membranes were yellow-pink and slightly dry. He was mildly tachypneic but respirations were otherwise unlabored with clear breath sounds bilaterally. Heart examination was normal. The abdomen was soft and nondistended with a smooth, firm liver edge palpable 3 cm below the right costal margin. Examinations of the genitalia and extremities were normal. His tone, power, and primitive reflexes all appeared within normal limits.


Complete blood count: WBC count, 9400/mm3 (neutrophils 41%, band forms 1%, lymphocytes 45%); hemoglobin, 16.0 g/dL; platelets, 66 000/mm3. PT and PTT were markedly prolonged at 50 seconds and 112 seconds, respectively. Fibrinogen, 200 mg/dL, fibrin split products were negative. Serum electrolytes: serum bicarbonate, 17 mEq/L; serum glucose, 52 mg/dL; otherwise normal. Hepatic function panel: unconjugated bilirubin, 13.1 mg/dL; conjugated bilirubin, 5.9 mg/dL; alanine aminotransferase, 115 U/L; aspartate aminotransferase, 126 U/L; alkaline phosphatase, 730 U/L; gamma-glutamyl transferase, 255 U/L; albumin, 2.0 mg/dL.


On admission, the infant received intravenous fluids and antibiotics. In addition he required a second dose of fresh frozen plasma for treatment of his coagulopathy. A repeat liver ultrasound was consistent with the earlier study. An ophthalmology examination was unremarkable. The blood culture from the referring hospital was positive for Escherichia coli and the baby received a full course of IV antibiotics.

Further testing revealed a specific underlying diagnosis that guided subsequent inpatient management.



The differential diagnosis for the systemically ill neonate is quite broad. Given the positive blood culture in the infant, sepsis must be considered first. Sepsis can cause many of the symptoms seen in the infant, including an acidosis, conjugated hyperbilirubinemia, and liver dysfunction. It can also lead to disseminated intravascular coagulation, which should be considered as a cause of this patient’s coagulopathy. However, fibrinogen and fibrin split products were normal, suggesting that the elevations in PT and PTT were more likely the result of synthetic liver dysfunction. Infectious etiologies seen in this period include bacterial (e.g., group B Streptococcus, staphylococci, E. coliListeria monocytogenes) and viral (e.g., herpes simplex virus, enterovirus) pathogens. Less often, fungi (e.g., Candida species) and other classes of organisms (e.g., parasites) are implicated.

Treatment of acute infection is crucial, but there are several other processes to consider when evaluating a critically ill neonate. Cardiac diseases, such as tachydysrhythmias and ductal-dependent anatomic lesions (e.g., coarctation of the aorta, hypoplastic left heart syndrome), may present early in life with profound cardiovascular compromise. Shock can also be seen in severely anemic infants following a placental catastrophe, major intracranial hemorrhage, or significant hemolysis. Multiorgan dysfunction can also result from perinatal asphyxia, neonatal surgical emergencies, and a multitude of endocrine and metabolic abnormalities, including congenital adrenal hyperplasia, glucose and electrolyte derangements, and inborn errors of metabolism.

While sepsis may account for this patient’s clinical picture, given the severity of the cholestasis and liver synthetic dysfunction, other causes of conjugated hyperbilirubinemia in the neonate should be considered. Among the possibilities are idiopathic neonatal hepatitis, alpha-1-antitrypsin deficiency, hypothyroidism, bile acid synthesis deficiency, and disorders of hepatobiliary anatomy. Neonatal hepatomegaly can also be seen with congenitally acquired (e.g., TORCH) infections, hydrops or congestive heart failure, tumors, and metabolic disease (e.g., glycogen storage diseases, galactosemia, tyrosinemia, and others).


Shortly after interhospital transfer, this baby’s state newborn screening results revealed him to have galactosemia.


Galactosemia is a rare inborn error of metabolism, occurring in 1 per 60 000 infants, caused by defects in galactose metabolism. Classic galactosemia is an autosomal recessive disease. If not recognized and treated, it can be fatal in the neonatal period. Although galactosemia is widely tested for in state newborn screening programs, the onset of life-threatening clinical illness may precede the completion of testing.

Galactosemia results from deficiencies in the enzymes involved in the metabolism of galactose. The hydrolysis of dietary lactose produces glucose and galactose. Galactose is subsequently phosphorylated to galactose-1-phosphate which is then converted by the galactose-1-phosphate uridyl transferase (GALT) enzyme to UDP-galactose. In “classic” galactosemia, GALT activity is completely absent and galactose-1-phosphate accumulates in the tissues leading to signs and symptoms of the disease. However, if partial GALT activity is present, as in a variant known as Duarte galactosemia, individuals may have no long-term clinical sequelae. The GALT gene has been mapped to 9p13 and more than 150 mutations have been identified. The most common allele is Q188R which causes severe disease. A milder form of galactosemia, found primarily in African-Americans, is caused by the S135L allele (Figure 15-8).


FIGURE 15-8. Simplified pathway of galactose metabolism. GALK, galactokinase; GALT, galactose-1-phosphate uridyltransferase; GALE, uridyl diphosphate galactose 4-epirimase; UDP, uridyl diphosphate.

Additionally, there are two other types of “nonclassic” galactosemia. Galactokinase (GALK) deficiency, a deficiency of the enzyme necessary for the phosphorylation of galactose, causes cataracts but does not result in mental deficiency. An even rarer type of galactosemia is caused by uridyl diphosphate galactose 4-epimerase (GALE) deficiency. This deficiency causes a spectrum of disease where affected individuals may be completely asymptomatic or may have features similar to those seen in “classic” galactosemia, with the addition of deafness and hypotonia (Table 15-8).

TABLE 15-8. Types of galactosemia.



Presenting signs in the galactose-exposed, affected neonate can include jaundice, hepatomegaly, seizures, lethargy, vomiting, hypoglycemia, cataracts, and failure to thrive. In addition, babies with galactosemia exhibit a heightened susceptibility to bacterial infection, particularly E. coli sepsis. Among the laboratory findings seen with classic galactosemia are conjugated (or combined) hyperbilirubinemia; liver function test and coagulation study abnormalities; elevations of serum and urine amino acids; and a renal tubulopathy with galactosuria, glycosuria, proteinuria, and metabolic acidosis. Plasma galactose and erythrocyte galactose-1-phosphate levels are also elevated.

Unfortunately, even galactosemic children whose diets are restricted very early are at increased risk of developmental delays and learning disabilities. Although the pathophysiology remains unclear, it is thought that continued endogenous production of galactose may contribute to some of these long-term sequelae. Though many children have IQs in the normal range, cognitive, speech, and motor impairments are common. Hypergonado-tropic hypogonadism is often observed in girls with galactosemia, and most are infertile as adults. Galactosemic boys demonstrate normal puberty and fertility.


Newborn screening. Every state in the United States screens for galactosemia. Most states use either a fluorometric assay to detect GALT activity or a bacterial inhibition assay to measure total galactose. Each method is associated with a number of false-positives and false-negatives. Results may be skewed if the infant fed poorly or was given soy formula, received a blood transfusion, or was given antibiotics. The fluorometric assay does not detect GALK or GALE deficiency.

RBC quantitative assay. Definitive diagnosis of classic galactosemia is established by laboratory assay of the GALT enzyme in erythrocytes. If there is clinical suspicion for galactosemia or the infant has had a positive newborn screen (often with a second screen for confirmation), the quantitative assay should be performed. If GALK or GALE deficiency is suspected, RBC assays for GALK and GALE activity should be performed.

Other testing. Prenatal testing for galactosemia is available, as is DNA analysis for some of the more common mutations. However, given the large number of mutations, a negative genetic screen does not exclude the disease. When clinical suspicion for galactosemia exists, preliminary evidence for that diagnosis can be obtained by testing the infant’s urine for nonglucose reducing substances (provided that the infant had recently been exposed to lactose). However, this test is neither sensitive nor specific for galactosemia.


The removal of galactose from the diet remains the first principle of therapy for galactosemia. Any infant with suspected galactosemia should immediately be changed from breastmilk or a milk-based formula to a soy or hydrolysate formula.

Depending on the degree of illness at the time of presentation, galactosemic neonates often require any number of supportive care measures such as intravenous fluids and antibiotics. Liver synthetic function may be compromised and the sick infant may require supplemental vitamin K or even transfusion of fresh frozen plasma. Patients with galactosemia should have long-term monitoring for potential ophthalmologic, neurodevelopmental, or endocrinologic complications.


1. Bosch AM, Grootenhuis MA, Bakker HD, et al. Living with classical galactosemia: health-related quality of life consequences. Pediatrics. 2004;113:e423-e428.

2. Ridel KR, Leslie ND, Gilbert DL. An updated review of the long-term neurological effects of galactosemia. Pediatr Neurol. 2005;33:153-161.

3. Shield JPH, Wadworth EJK, MacDonald A, et al. The relationship of genotype to cognitive outcome in galactosemia. Arch Dis Child. 2000;83:248-250.

4. Sutton VR. Clinical features and diagnosis of galactosemia. UpToDate. Updated July 16, 2010. Accessed September 15, 2011.

5. Walter JH, Collins JE, Leonard JV. Recommendations for the management of galactosaemia. Arch Dis Child. 1999;80:93-96.